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Abstract:

The invention relates to N-hydroxylsulfonamide derivatives that donate
nitroxyl (HNO) under physiological conditions and are useful in treating
and/or preventing the onset and/or development of diseases or conditions
that are responsive to nitroxyl therapy, including heart failure and
ischemia/reperfusion injury. Novel N-hydroxylsulfonamide derivatives
release NHO at a controlled rate under physiological conditions, and the
rate of HNO release is modulated by varying the nature and location of
functional groups on the N-hydroxylsulfonamide derivatives.

Claims:

1-13. (canceled)

14. A compound of the formula (I), (II) or ##STR00116## or a
pharmaceutically acceptable salt thereof, wherein: R1 is H; R2
is H, aralkyl or heterocyclyl; m and n are independently an integer from
0 to 2; x is an integer from 0 to 4 and y is an integer from 0 to 3,
provided that at least one of x and y is greater than 0; b is an integer
from 1-4; R3, R4, R5, R6 and R7 areindependently
selected from the group consisting of H, halo, alkylsulfonyl,
N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy,
perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl,
heterocycloalkyl, substituted heterocycloalkyl, dialkylamino,
cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, arylsulfinyl, carboxyl,
carboxyl ester, acylamino and sulfonylamino, provided that at least one
of R3, R4, R5, R6 and R7 is carboxyl, carboxyl
ester, acylamino or sulfonylamino; each R8 and R9 is
independently selected from the group consisting of halo, alkylsulfonyl,
N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy,
perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl,
heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, NH2,
OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH2,
NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH2,
OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N--OH)NH2, cycloalkoxy,
cycloalkylsulfanyl, arylsulfanyl, arylsulfinyl, carbonylamino and
sulfonylamino, provided that: (1) at least one R8 is carbonylamino
or sulfonylamino when the compound is of the formula (III) and (2) at
least one of R8 and R9 is carbonylamino or sulfonylamino when
the compound is of the formula (II); A is a cycloalkyl, heterocycloalkyl,
aromatic or heteroaromatic ring containing ring moieties Q1,
Q2, Q3 and Q4, which are taken together with V and W to
form ring A; B is a cycloalkyl, heterocycloalkyl, aromatic or
heteroaromatic ring containing ring moieties Q5, Q6, Q7
and Q8, which are taken together with the V and W to form ring B; V
and W are independently C, CH, N or NR10; Q1, Q2, Q3,
Q4, Q5, Q6, Q7and Q8 are independently selected
from the group consisting of C, CH2, CH, N, NR10, O and S; C is
a heteroaromatic ring containing ring moieties Q9, Q10,
Q11, Q12, Q13 and Q14 that are independently selected
from the group consisting of C, CH2, CH, N, NR10, O and S,
provided that at least one of Q9, Q10, Q11, Q12,
Q13 and Q14 is N, NR10, O or S, and R10 is H, alkyl,
acyl or sulfonyl.

15. The compound of claim 14, wherein R2 is H.

16. The compound of claim 14, wherein x and y are both 1.

17. The compound of claim 14, wherein the compound is of the formula (I).

18. The compound of claim 17, wherein the compound is of the formula (I)
and at least one of R3 and R7 is other than H.

19. The compound of claim 17, wherein the compound is of the formula (I)
and at least one of Wand R7 is an electron withdrawing group.

20. The compound of claim 17, wherein the compound is of the formula (I)
and at least one of R3, R4, R5, R6 and R7 is
carboxyl, --COO-alkyl, --C(O)NH2, --C(O) NRaRb where
Ra is hydrogen and Rb is alkyl, --C(O)NRaRb where
Ra and Rb are independently alkyl, --C(O)NRaRb where
Ra and Rb are taken together with the nitrogen to which they
are attached to form a heterocyclic or substituted heterocyclic ring,
--SO2NH2, --SO2NR-alkyl where R is hydrogen,
--SO2NR-alkyl where R is alkyl, --SO2NR2, where the two R
groups are taken together with the nitrogen to which they are attached to
form a heterocyclic or substituted heterocyclic ring.

21. The compound of claim 14, wherein the compound is of the formula
(II).

22. The compound of claim 14, wherein the compound is of the formula
(III).

30. A method of modulating the in vivo nitroxyl levels in an individual
in need thereof, the method comprising administering to the individual an
N-hydroxysulfonamide of claim 14 or a pharmaceutically acceptable salt
thereof.

31. A method of treating, preventing or delaying the onset or development
of a disease or condition that is responsive to nitroxyl therapy,
comprising administering to an individual in need thereof a compound of
claim 14 or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising a compound of claim 14 and a
pharmaceutically acceptable carrier.

33. A kit comprising a compound of the claim 14 and instructions for use
in the treatment of a disease or condition that is responsive to nitroxyl
therapy.

Description:

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent
Application Ser. No. 60/995,636, filed Sep. 26, 2007 and entitled,
"N-Hydroxylsulfonamide Derivatives as New Physiologically Useful Nitroxyl
Donors," which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Summary of Heart Failure

[0003] Congestive heart failure (CHF) is a generally progressive, life
threatening condition in which myocardial contractility is depressed such
that the heart is unable to adequately pump the blood returning to it,
also referred to as decompensation. Symptoms include breathlessness,
fatigue, weakness, leg swelling, and exercise intolerance. On physical
examination, patients with heart failure often have elevated heart and
respiratory rates (an indication of fluid in the lungs), edema, jugular
venous distension, and enlarged hearts. The most common cause of CHF is
atherosclerosis, which causes blockages in the coronary arteries that
provide blood flow to the heart muscle. Ultimately, such blockages may
cause myocardial infarction with subsequent decline in heart function and
resultant heart failure. Other causes of CHF include valvular heart
disease, hypertension, viral infections of the heart, alcohol
consumption, and diabetes. Some cases of CHF occur without clear etiology
and are called idiopathic. The effects of CHF on a subject experiencing
the condition can be fatal.

[0004] There are several types of CHF. Two types of CHF are identified
according to which phase of the cardiac pumping cycle is more affected.
Systolic heart failure occurs when the heart's ability to contract
decreases. The heart cannot pump with enough force to push a sufficient
amount of blood into the circulation leading to a reduced left
ventricular ejection fraction. Lung congestion is a typical symptom of
systolic heart failure. Diastolic heart failure refers to the heart's
inability to relax between contractions and allow enough blood to enter
the ventricles. Higher filling pressures are required to maintain cardiac
output, but contractility as measured by left ventricular ejection
fraction is typically normal. Swelling (edema) in the abdomen and legs is
a typical symptom of diastolic heart failure. Often, an individual
experiencing heart failure will have some degree of both systolic heart
failure and diastolic heart failure.

[0005] CHF is also classified according to its severity. The New York
Heart Association classifies CHF into four classes: Class I involves no
obvious symptoms, with no limitations on physical activity; Class II
involves some symptoms during or after normal activity, with mild
physical activity limitations; Class III involves symptoms with less than
ordinary activity, with moderate to significant physical activity
limitations; and Class IV involves significant symptoms at rest, with
severe to total physical activity limitations. Typically, an individual
progresses through the classes as they live with the condition.

[0006] Although CHF is generally thought of as a chronic, progressive
condition, it can also develop suddenly. This type of CHF is called acute
CHF, and it is a medical emergency. Acute CHF can be caused by acute
myocardial injury that affects either myocardial performance, such as
myocardial infarction, or valvular/chamber integrity, such as mitral
regurgitation or ventricular septal rupture, which leads to an acute rise
in left ventricular and diastolic pressure resulting in pulmonary edema
and dyspnea.

[0008] Positive inotropic agents include beta-adrenergic agonists, such as
dopamine, dobutamine, dopexamine, and isoproterenol. However, use of a
beta-agonist has potential complications, such as arrhythmogenesis and
increased oxygen demand by the heart. Additionally, the initial
short-lived improvement of myocardial contractility afforded by these
drugs is followed by an accelerated mortality rate resulting largely from
a greater frequency of sudden death. Katz, HEART FAILURE:
PATHOPHYSIOLOGY, MOLECULAR BIOLOGY AND CLINICAL MANAGEMENT, Lippincott,
Williams & Wilkins (1999).

[0009] Beta-antagonists antagonize beta-adrenergic receptor function.
While initially contra-indicated in heart failure, they have been found
to provide a marked reduction in mortality and morbidity in clinical
trials. Bouzamondo et al., Fundam. Clin. Pharmacol., 15: 95-109 (2001).
Accordingly, they have become an established therapy for heart failure.
However, even subjects that improve under beta-antagonist therapy may
subsequently decompensate and require acute treatment with a positive
inotropic agent. Unfortunately, as their name suggests, beta-antagonists
block the mechanism of action of the positive inotropic beta-agonists
that are used in emergency care centers. Bristow et al., J. Card. Fail.,
7: 8-12 (2001).

[0010] Vasodilators, such as nitroglycerin, have been used for a long
period of time to treat heart failure. However, the cause of
nitroglycerin's therapeutic effect was not known until late in the last
century when it was discovered that the nitric oxide molecule (NO) was
responsible for nitroglycerin's beneficial effects. In some subjects
experiencing heart failure, a nitric oxide donor is administered in
combination with a positive inotropic agent to both cause vasodilation
and to increase myocardial contractility. However, this combined
administration can impair the effectiveness of positive inotropic
treatment agents. For example, Hart et al, Am. J. Physiol. Heart Circ.
Physiol., 281:146-54 (2001) reported that administration of the nitric
oxide donor sodium nitroprusside, in combination with the positive
inotropic, beta-adrenergic agonist dobutamine, impaired the positive
inotropic effect of dobutamine. Hare et al., Circulation, 92:2198-203
(1995) also disclosed the inhibitory effect of nitric oxide on the
effectiveness of dobutamine.

[0011] As described in U.S. Pat. No. 6,936,639, compounds that donate
nitroxyl (HNO) under physiological conditions have both positive
inotropic and lusitropic effects and offer significant advantages over
existing treatments for failing hearts. Due to their concomitant positive
inotropic/lusotropic action and unloading effects, nitroxyl donors were
reported as helpful in treating cardiovascular diseases characterized by
high resistive load and poor contractile performance. In particular,
nitroxyl-donating compounds were reported as useful in the treatment of
heart failure, including heart failure in individuals receiving
beta-antagonist therapy.

Summary of Ischemia

[0012] Ischemia is a condition characterized by an interruption or
inadequate supply of blood to tissue, which causes oxygen deprivation in
the affected tissue. Myocardial ischemia is a condition caused by a
blockage or constriction of one or more of the coronary arteries, such as
can occur with atherosclerotic plaque occlusion or rupture. The blockade
or constriction causes oxygen deprivation of the non-perfused tissue,
which can cause tissue damage. Further, upon reperfusion with subsequent
reoxygenation of the tissue, when the blood is able to flow again or the
oxygen demand of the tissue subsides, additional injury can be caused by
oxidative stress.

[0013] Ischemia/reperfusion injury refers to tissue damage caused by
oxygen deprivation followed by reoxygenation. The effects of
ischemia/reperfusion injury in a subject experiencing the condition can
be fatal, particularly when the injury occurs in a critical organ such as
the heart or brain.

[0014] Accordingly, compounds and compositions effective in preventing or
protecting against ischemia/reperfusion injury would be useful
pharmaceuticals. Compounds such as nitroglycerin have been used for a
long period of time to help control vascular tone and protect against
myocardial ischemia/reperfusion injury. It was discovered that the nitric
oxide molecule was responsible for nitroglycerin's beneficial effects.
This discovery prompted interest in medical uses for nitric oxide and
investigations into related species such as nitroxyl. As reported in U.S.
patent application Ser. No. 10/463,084 (U.S. Publication No.
2004/0038947) administration of a compound that donates nitroxyl under
physiological conditions, prior to ischemia, can attenuate
ischemia/reperfusion injury to tissues, for example, myocardial tissues.
This beneficial effect was reported as a surprising result given that
nitroxyl was previously reported to increase ischemia/reperfusion injury
(See, Ma et al., "Opposite Effects of Nitric Oxide and Nitroxyl on
Postischemic Myocardial Injury," Proc. Nat'l Acad. Sci., 96(25):
14617-14622 (1999), reporting that administration of Angeli's salt (a
nitroxyl donor under physiological conditions) to anesthetized rabbits
during ischemia and 5 minutes prior to reperfusion increased myocardial
ischemia/reperfusion injury and Takahira et al., "Dexamethasone
Attenuates Neutrophil Infiltration in the Rat Kidney in
Ischemia/Reperfusion Injury: The Possible Role of Nitroxyl," Free Radical
Biology & Medicine, 31(6):809-815 (2001) reporting that administration of
Angeli's salt during ischemia and 5 minutes before reperfusion of rat
renal tissue contributed to neutrophil infiltration into the tissue,
which is believed to mediate ischemia/reperfusion injury). In particular,
pre-ischemic administration of Angeli's salt and isopropylamine/NO has
been reported to prevent or reduce ischemia/reperfusion injury.

Summary of Nitroxyl Donors

[0015] To date, the vast majority of studies of the biological effect of
HNO have used the donor sodium dioxotrinitrate ("Angeli's salt" or "AS").
However, the chemical stability of AS has made it unsuitable to develop
as a therapeutic agent. N-hydroxybenzenesulfonamide ("Piloty's acid" or
"PA") has previously been shown to be a nitroxyl donor at high ph (>9)
(Bonner, F. T.; Ko, Y. Inorg. Chem. 1992, 31, 2514-2519). However, under
physiological conditions, PA is a nitric oxide donor via an oxidative
pathway (Zamora, R.; Grzesiok, A.; Weber, H.; Feelisch, M. Biochem. J.
1995, 312, 333-339). Thus, the physiological effects of AS and PA are not
the same because AS is a nitroxyl donor under physiological conditions
whereas PA is a nitric oxide donor under physiological conditions.

[0016] Although U.S. Pat. No. 6,936,639 and U.S. Publication No.
2004/0038947 describe PA as a compound that donates nitroxyl and note
that other sulfohydroxamic acids and their derivatives are therefore also
useful as nitroxyl donors, PA does not in fact donate significant amounts
of nitroxyl under physiological conditions (See Zamora, supra).

[0018] N-hydroxylsulfonamide derivatives as new physiologically useful
nitroxyl donors are also described in PCT application No.
PCT/US2007/006710 filed Mar.16, 2007. However, compounds of the formula
(I) described therein are not substituted with at least one carboxyl,
carboxyl ester, acylamino or sulfonylamino group and compounds of the
formula (II) or (III) described therein are not substituted with at least
one carbonylamino or sulfonylamino group.

Significant Medical Need

[0019] Despite efforts towards the development of new therapies for the
treatment of diseases and conditions such as heart failure and
ischemia/reperfusion injury, there remains a significant interest in and
need for additional or alternative compounds that treat or prevent the
onset or severity of these and related diseases or conditions. In
particular, there remains a significant medical need for alternative or
additional therapies for the treatment of diseases or conditions that are
responsive to nitroxyl therapy. New compounds that donate nitroxyl under
physiological conditions and methods of using compounds that donate
nitroxyl under physiological conditions may thus find use as therapies
for treating, preventing and/or delaying the onset and/or development of
diseases or conditions responsive to nitroxyl therapy, including heart
disease and ischemia/reperfusion injury. Preferably, the therapeutic
agents can improve the quality of life and/or prolong the survival time
for patients with the disease or condition.

BRIEF SUMMARY OF THE INVENTION

[0020] Methods, compounds and compositions for treating and/or preventing
the onset or development of diseases or conditions that are responsive to
nitroxyl therapy are described. Aromatic and non-aromatic
N-hydroxylsulfonamide derivatives that donate nitroxyl under
physiological conditions are described. By modifying PA with appropriate
substituents, such as electron-withdrawing groups or groups that
sterically hinder the sulfonyl moiety, the HNO producing capacity of
these derivatives is substantially enhanced under physiological
conditions. Significantly, when compared to AS, PA has the capacity for
broad substituent modification, enabling optimization of physicochemical
and pharmacological properties. Such optimization is reported herein.

[0021] In one embodiment, the present invention provides a method of
administering to a subject in need thereof, a therapeutically effective
amount of a derivative of PA wherein the derivative donates nitroxyl
under physiological conditions. In one embodiment, the invention embraces
a method of treating or preventing the onset and/or development of a
disease or condition that is responsive to nitroxyl therapy, the method
comprising administering to an individual in need thereof an
N-hydroxylsulfonamide that donates an effective amount of nitroxyl under
physiological conditions. Also embraced are methods of treating heart
failure or ischemia/reperfusion injury by administering to an individual
in need thereof an N-hydroxysulfonamide that donates an effective amount
of nitroxyl under physiological conditions.

[0022] Kits comprising the compounds are also described, which may
optionally contain a second therapeutic agent such as a positive
inotropic compound, which may be, e.g., a beta-adrenergic receptor
agonist.

[0023] Novel compounds that find use in the invention described herein
include compounds of the formula (I), (II) or (III):

##STR00001##

[0024] where R1 is H; R2 is H, aralkyl or heterocyclyl; m and n
are independently an integer from 0 to 2; x is an integer from 0 to 4 and
y is an integer from 0 to 3, provided that at least one of x and y is
greater than 0; b is an integer from 1-4; R3, R4, R5,
R6 and R7 are independently selected from the group consisting
of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro,
aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy,
alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted
heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl,
arylsulfanyl, arylsulfinyl, carboxyl, carboxyl ester, acylamino and
sulfonylamino, provided that at least one of R3, R4, R5,
R6 and R7 is carboxyl, carboxyl ester, acylamino or
sulfonylamino; each R8 and R9 is independently selected from
the group consisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl,
perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl,
substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl,
substituted heterocycloalkyl, dialkylamino, NH2, OH, C(O)OH,
C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH2, NHC(O)alkylC(O)alkyl,
NHC(O)alkenylC(O)OH, NHC(O)NH2, OalkylC(O)Oalkyl, NHC(O)alkyl,
C(═N--OH)NH2, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl,
arylsulfinyl, carbonylamino, and sulfonylamino, provided that: (1) at
least one R8 is carbonylamino or sulfonylamino when the compound is
of the formula (III) and (2) at least one of R8 and R9 is
carbonylamino or sulfonylamino when the compound is of the formula (II);
A is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring
containing ring moieties Q1, Q2, Q3 and Q4, which are
taken together with V and W to form ring A; B is a cycloalkyl,
heterocycloalkyl, aromatic or heteroaromatic ring containing ring
moieties Q5, Q6, Q7 and Q8, which are taken together
with the V and W to form ring B; V and W are independently C, CH, N or
NR10; Q1, Q2, Q3, Q4, Q5, Q6, Q7
and Q8 are independently selected from the group consisting of C,
CH2, CH, N, NR10, O and S; C is a heteroaromatic ring
containing ring moieties Q9, Q10, Q11, Q12, Q13
and Q14 that are independently selected from the group consisting of
C, CH2, CH, N, NR10, O and S, provided that at least one of
Q9, Q10, Q11, Q12, Q13 and Q14 is N,
NR10, O or S; and R10 is H, alkyl, acyl or sulfonyl.
Pharmaceutically acceptable salts of any of the foregoing are also
described.

[0025] In one variation, the compound is of the formula (I), (II) or (III)
where R1 is H; R2 is H; m and n are independently an integer
from 0 to 2; x is an integer from 0 to 4 and y is an integer from 0 to 3,
provided that at least one of x and y is greater than 0; b is an integer
from 1-4; R3, R4, R5, R6 and R7 are
independently selected from the group consisting of H, halo,
alkylsulfonyl, substituted alkylsulfonyl, N-hydroxylsulfonamidyl,
substitued N-hydroxylsulfonamidyl, perhaloalkyl, substituted perhaloalkyl
(where one or more halo may be substituted with a substituent), nitro,
aryl, substituted aryl, cyano, alkoxy, substituted alkoxy, perhaloalkoxy,
substituted perhaloalkoxy, alkyl, substituted alkyl, aryloxy, substituted
aryloxy, alkylsulfanyl, substituted alkylsulfanyl, alkylsulfinyl,
substituted alkylsulfinyl, heterocycloalkyl, substituted
heterocycloalkyl, dialkylamino, substituted dialkylamino, cycloalkoxy,
substituted cycloalkoxy, cycloalkylsulfanyl, substituted
cycloalkylsulfanyl, arylsulfanyl, substituted arylsulfanyl, arylsulfinyl,
substituted arylsulfinyl, carboxyl, carboxyl ester, acylamino and
sulfonylamino, provided that at least one of R3, R4, R5,
R6 and R7 is carboxyl, carboxyl ester, acylamino or
sulfonylamino; each R8 and R9 is independently selected from
the group consisting of halo, alkylsulfonyl, substituted alkylsulfonyl,
N-hydroxylsulfonamidyl, substituted N-hydroxylsulfonamidyl, perhaloalkyl,
substituted perhaloalkyl, nitro, aryl, substituted aryl, cyano, alkoxy,
substituted alkoxy, perhaloalkoxy, substituted perhaloalkoxy, alkyl,
substituted alkyl, aryloxy, substituted aryloxy, alkylsulfanyl,
substituted alkylsulfanyl, alkylsulfinyl, substituted alkylsulfinyl,
heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, substituted
dialkylamino, NH2, OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH,
C(O)NH2, NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH2,
OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N--OH)NH2, cycloalkoxy,
substituted cycloalkoxy, cycloalkylsulfanyl, substituted
cycloalkylsulfanyl, arylsulfanyl, substituted arylsulfanyl, arylsulfinyl,
substituted arylsulfinyl (where any listing of alkyl or alkenyl in the
moieties above intends unsubstituted or substituted alkyl or alkenyl),
carbonylamino and sulfonylamino, provided that: (1) at least one R8
is carbonylamino or sulfonylamino when the compound is of the formula
(III) and (2) at least one of R8 and R9 is carbonylamino or
sulfonylamino when the compound is of the formula (II); A is a
cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing
ring moieties Q1, Q2, Q3 and Q4, which are taken
together with V and W to form ring A; B is a cycloalkyl,
heterocycloalkyl, aromatic or heteroaromatic ring containing ring
moieties Q5, Q6, Q7 and Q8, which are taken together
with the V and W to form ring B; V and W are independently C, CH, N or
NR10; Q1, Q2, Q3, Q4, Q5, Q6,
Q7and Q8 are independently selected from the group consisting
of C, CH2, CH, N, NR10, O and S; C is a heteroaromatic ring
containing ring moieties Q9, Q10, Q11, Q12, Q13
and Q14 that are independently selected from the group consisting of
C, CH2, CH, N, NR10, O and S, provided that at least one of
Q9, Q10, Q11, Q12, Q13 and Q14 is N,
NR10, O or S; and R10 is H, alkyl, acyl or sulfonyl.
Pharmaceutically acceptable salts of any of the foregoing are also
described.

[0026] Methods of using the compounds detailed herein are also described,
including a method of treating, preventing or delaying the onset or
development of a disease or condition that is responsive to nitroxyl
therapy, comprising administering to an individual in need thereof a
compound of the invention that donates nitroxyl under physiological
conditions or a pharmaceutically acceptable salt thereof.

[0027] Pharmaceutical compositions comprising a compound of the invention
are disclosed, such as pharmaceutical compositions that are amenable to
intravenous injection. Kits comprising a compound of the invention and
instructions for use are also described.

BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG. 1 illustrates the nitrous oxide evolved from Compounds 1-5 as
a percent of Angeli's Salt and the mole percent of N2O generated per
mole of sample for compounds 1-5.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0029] Unless clearly indicated otherwise, the following terms as used
herein have the meanings indicated below.

[0030] Use of the terms "a", "an" and the like refers to one or more.

[0031] "Aralkyl" refers to a residue in which an aryl moiety is attached
to the parent structure via an alkyl residue. Examples include benzyl
(--CH2--Ph), phenethyl (--CH2CH2Ph), phenylvinyl
(--CH═CH--Ph), phenylallyl and the like.

[0033] "Heterocyclyl" or "Heterocycloalkyl" refers to a cycloalkyl residue
in which one to four of the carbons is replaced by a heteroatom such as
oxygen, nitrogen or sulfur. Examples of heterocycles whose radicals are
heterocyclyl groups include tetrahydropyran, morpholine, pyrrolidine,
piperidine, thiazolidine, oxazole, oxazoline, isoxazole, dioxane,
tetrahydrofuran and the like. A specific example of a heterocyclyl
residue is tetrahydropyran-2-yl.

[0034] "Substituted heterocyclo" or "substituted heterocylcoalkyl" refers
to an heterocyclyl group having from 1 to 5 substituents. For instance, a
heterocyclyl group substituted with 1 to 5 groups such as halo, nitro,
cyano, oxo, aryl, alkoxy, alkyl, acyl, acylamino, amino, hydroxyl,
carboxyl, carboxylalkyl, thiol, thioalkyl, heterocyclyl,
--OS(O)2-alkyl, and the like is a substituted alkyl. A particular
example of a substituted heterocylcoalkyl is N-methylpiperazino.

[0035] "Alkyl" intends linear hydrocarbon structures having 1 to 20 carbon
atoms, preferably 1 to 12 carbon atoms and more preferably 1 to 8 carbon
atoms. Alkyl groups of fewer carbon atoms are embraced, such as so-called
"lower alkyl" groups having 1 to 4 carbon atoms. "Alkyl" also intends
branched or cyclic hydrocarbon structures having 3 to 20 carbon atoms,
preferably 3 to 12 carbon atoms and more preferably 3 to 8 carbon atoms.
For any use of the term "alkyl," unless clearly indicated otherwise, it
is intended to embrace all variations of alkyl groups disclosed herein,
as measured by the number of carbon atoms, the same as if each and every
alkyl group was explicitly and individually listed for each usage of the
term. For instance, when a group such as R3 may be an "alkyl,"
intended is a C1-C20 alkyl or a C1-C12 alkyl or a
C1-C5 alkyl or a lower alkyl or a C2-C20 alkyl or a
C3-C12 alkyl or a C3-C8 alkyl. The same is true for
other groups listed herein, which may include groups under other
definitions, where a certain number of atoms is listed in the definition.
When the alkyl group is cyclic, it may also be referred to as a
cycloalkyl group and have e.g., 3 to 20 annular carbon atoms, preferably
3 to 12 annular carbon atoms and more preferably 3 to 8 annular carbon
atoms. When an alkyl residue having a specific number of carbons is
named, all geometric isomers having that number of carbons are intended
to be encompassed; thus, for example, "butyl" is meant to include
n-butyl, sec-butyl, iso-butyl and t-butyl; "propyl" includes n-propyl and
iso-propyl. Examples of alkyl groups include methyl, ethyl, n-propyl,
i-propyl, t-butyl, n-heptyl, octyl, cyclopentyl, cyclopropyl, cyclobutyl,
norbornyl, and the like. One or more degrees of unsaturation may occur in
an alkyl group. Thus, an alkyl group also embraces alkenyl and alkynyl
residues. "Alkenyl" is understood to refer to a group of 2 or more carbon
atoms, such as 2 to 10 carbon atoms and more preferably 2 to 6 carbon
atoms and having at least 1 and preferably from 1-2 sites of alkenyl
unsaturation. Examples of an alkenyl group include --C═CH2,
--CH2CH═CHCH3 and --CH2CH═CH--CH═CH2.
"Alkynyl" refers to alkynyl group preferably having from 2 to 10 carbon
atoms and more preferably 3 to 6 carbon atoms and having at least 1 and
preferably from 1-2 sites of alkynyl unsaturation, such as the moiety
--C═CH. Alkyl is also used herein to denote an alkyl residue as part
of a larger functional group and when so used, is taken together with
other atoms to form another functional group. For instance, reference to
--C(O)Oalkyl intends an ester functional group, where the alkyl portion
of the moiety may be any alkyl group, and provide by way of example only,
the functional group --C(O)OCH3, --C(O)(O)CH═CH2 and the
like. Another example of an alkyl group as part of a larger structure
includes the residue --NHC(O)alkylC(O)OH, which e.g., may be
NHC(O)CH2CH2C(O)OH when alkyl is --CH2CH2--.

[0036] "Substituted alkyl" refers to an alkyl group having from 1 to 5
substituents. For instance, an alkyl group substituted with a group such
as halo, nitro, cyano, oxo, aryl, alkoxy, acyl, acylamino, amino,
hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkyl, heterocyclyl,
--OS(O)2-alkyl, and the like is a substituted alkyl. Likewise,
"substituted alkenyl" and "substituted alkynyl" refer to alkenyl or
alkynyl groups having 1 to 5 substituents.

[0038] "Electron withdrawing group" refers to groups that reduce electron
density of the moiety to which they are attached (relative to the density
of the moiety without the substituent). Such groups include, for example,
F, Cl, Br, I, --CN, --CF3, --NO2, --SH, --C(O)H, --C(O)alkyl,
--C(O)Oalkyl, --C(O)OH, --C(O)Cl, --S(O)2OH, --S(O)2NHOH,
--NH3 and the like.

[0044] "Substituted aryl" refers to a group having from 1 to 3
substituents. For instance, an aryl group substituted with 1 to 3 groups
such as halo, nitro, cyano, oxo, aryl, alkoxy, alkyl, acyl, acylamino,
amino, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkyl, heterocyclyl,
--OS(O)2-alkyl, and the like is a substituted aryl.

[0045] "Alkoxy" refers to an alkyl group that is connected to the parent
structure through an oxygen atom (--O-alkyl). When a cycloalkyl group is
connected to the parent structure through an oxygen atom, the group may
also be referred to as a cycloalkoxy group. Examples include methoxy,
ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
A "perhaloalkoxy" intends a perhaloalkyl group attached to the parent
structure through an oxygen, such as the residue --O--CF3.

[0046] "Aryloxy" refers to an aryl group that is connected to the parent
structure through an oxygen atom (--O--aryl), which by way of example
includes the residues phenoxy, naphthoxy, and the like. "Substituted
aryloxy" refers to a substituted aryl group connected to the parent
structure through an oxygen atom (--O-substituted aryl).

[0047] "Alkylsulfanyl" refers to an alkyl group that is connected to the
parent structure through a sulfur atom (--S-alkyl) and refers to groups
--S-alkyl and --S-substituted alkyl, which includes the residues
--S-cycloalkyl, --S-substituted cycloalkyl, --S-alkenyl, --S-substituted
alkenyl, --S-alkynyl, --S-substituted alkynyl, where alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl and substituted cycloalkyl are as defined herein. When a
cycloalkyl group is connected to the parent structure through an sulfur
atom, the group may also be referred to as a cycloalkylsulfanyl group. By
way of example, alkylsulfanyl includes --S--CH(CH3),
--S--CH2CH3 and the like.

[0048] "Alkylsulfinyl" refers to an alkyl group that is connected to the
parent structure through a S(O) moiety and refers to groups --S(O)alkyl
and --S(O)substituted alkyl, which includes the residues
--S(O)cycloalkyl, --S(O)substituted cycloalkyl, --S(O)alkenyl,
--S(O)substituted alkenyl, --S(O)alkynyl, --S(O)substituted alkynyl,
where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl and substituted cycloalkyl are as defined
herein. By way of example, alkylsulfinyl includes the residues
--S(O)CH(CH3), --S(O)CH3, --S(O)cyclopentane and the like.

[0049] "Arylsulfinyl" refers to an aryl group that is connected to the
parent structure through a S(O) moiety, which by way of example includes
the residue --S(O)Ph.

[0050] "Dialkylamino" refers to the group --NR2 where each R is an
alkyl group. Examples of dialkylamino groups include --N(CH3)2,
--N(CH2CH2CH2CH3)2, and
N(CH3)(CH2CH2CH2CH3).

[0053] "Acylamino" refers to the group --C(O)NRaRb where each
Ra and Rb group is independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, substituted
heterocyclic or Ra and Rb groups can be joined together with
the nitrogen atom to form a heterocyclic or substituted heterocyclic
ring. An examples of an acylamino moiety includes --C(O)morpholino.

[0054] "Sulfonylamino" refers to the groups --SO2NH2,
--SO2NR-alkyl, --SO2NR-substituted alkyl, --SO2NR-alkenyl,
--SO2NR-substituted alkenyl, --SO2NR-alkynyl,
--SO2NR-substituted alkynyl, --SO2NR-aryl,
--SO2NR-substituted aryl, --SO2NR-heteroaryl,
--SO2NR-substituted heteroaryl, --SO2NR-heterocyclic, and
--SO2NR-substituted heterocyclic where R is hydrogen or alkyl, or
--SO2NR2, where the two R groups are taken together and with
the nitrogen atom to which they are attached to form a heterocyclic or
substituted heterocyclic ring.

[0055] "Carbonylamino" refers to the groups --CONH2, --CONR-alkyl,
--CONR-substituted alkyl, --CONR-alkenyl, --CONR-substituted alkenyl,
--CONR-alkynyl, --CONR-substituted alkynyl, --CONR-aryl,
--CONR-substituted aryl, --CONR-heteroaryl, --CONR-substituted
heteroaryl, --CONR-heterocyclic, and --CONR-substituted heterocyclic
where R is hydrogen or alkyl, or --CONR2, where the two R groups are
taken together and with the nitrogen atom to which they are attached to
form a heterocyclic or substituted heterocyclic ring.

[0056] "Pharmaceutically acceptable salt" refers to pharmaceutically
acceptable salts of a compound described herein, such as a compound of
Formula (I), (II) or (III) or other nitroxyl donor of the invention,
which salts may be derived from a variety of organic and inorganic
counter ions well known in the art and include, by way of example only,
sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and
the like; when the molecule contains a basic functionality, salts of
organic or inorganic acids, such as hydrochloride, hydrobromide,
tartrate, mesylate, acetate, maleate, oxalate and the like. Illustrative
salts include, but are not limited, to sulfate, citrate, acetate,
chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,
lactate, salicylate, acid citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate, besylate,
fumarate, gluconate, glucaronate, saccharate, formate, benzoate,
glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and
p-toluenesulfonate salts. Accordingly, a salt may be prepared from a
compound of any one of the formulae disclosed herein having an acidic
functional group, such as a carboxylic acid functional group, and a
pharmaceutically acceptable inorganic or organic base. Suitable bases
include, but are not limited to, hydroxides of alkali metals such as
sodium, potassium, and lithium; hydroxides of alkaline earth metal such
as calcium and magnesium; hydroxides of other metals, such as aluminum
and zinc; ammonia, and organic amines, such as unsubstituted or
hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;
tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine;
triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such
as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine,
or tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy lower
alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl) amine, or
tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as
arginine, lysine, and the like. A salt may also be prepared from a
compound of any one of the formulae disclosed herein having a basic
functional group, such as an amino functional group, and a
pharmaceutically acceptable inorganic or organic acid. Suitable acids
include hydrogen sulfate, citric acid, acetic acid, hydrochloric acid
(HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid,
phosphoric acid, lactic acid, salicylic acid, tartaric acid, ascorbic
acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic
acid, glucaronic acid, formic acid, benzoic acid, glutamic acid,
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and
p-toluenesulfonic acid.

[0057] Unless clearly indicated otherwise, "an individual" as used herein
intends a mammal, including but not limited to a human.

[0058] The term "effective amount" intends such amount of a compound or a
pharmaceutically acceptable salt thereof, which in combination with its
parameters of efficacy and toxicity, as well as based on the knowledge of
the practicing specialist should be effective in a given therapeutic
form. As is understood in the art, an effective amount may be in one or
more doses.

[0059] As used herein, "treatment" or "treating" is an approach for
obtaining a beneficial or desired result, including clinical results. For
purposes of this invention, beneficial or desired results include but are
not limited to inhibiting and/or suppressing the onset and/or development
of a disease or condition that is responsive to nitroxyl therapy or
reducing the severity of such disease or condition, such as reducing the
number and/or severity of symptoms associated with the disease or
condition, increasing the quality of life of those suffering from the
disease or condition, decreasing the dose of other medications required
to treat the disease or condition, enhancing the effect of another
medication an individual is taking for the disease or condition and
prolonging survival of individuals having the disease or condition. The
disease or condition may be a cardiovascular disease or condition, which
includes, but is not limited to, coronary obstructions, coronary artery
disease (CAD), angina, heart attack, myocardial infarction, high blood
pressure, ischemic cardiomyopathy and infarction, diastolic heart
failure, pulmonary congestion, pulmonary edema, cardiac fibrosis,
valvular heart disease, pericardial disease, circulatory congestive
states, peripheral edema, ascites, Chagas' disease, ventricular
hypertrophy, heart valve disease, heart failure, including but not
limited to congestive heart failure such as acute congestive heart
failure and acute decompensated heart failure. Related symptoms that may
be alleviated by the methods herein include shortness of breath, fatigue,
swollen ankles or legs, angina, loss of appetite, weight gain or loss,
associated with aforementioned diseases or disorders. The disease or
condition may involve ischemia/reperfusion injury.

[0060] As used herein, "preventing" refers to reducing the probability of
developing a disorder or condition in an individual who does not have,
but is at risk of developing a disorder or condition."

[0061] An individual "at risk" may or may not have a detectable disease or
condition, and may or may not have displayed a detectable disease or
condition prior to the treatment methods described herein. "At risk"
denotes that an individual has one or more so-called risk factors, which
are measurable parameters that correlate with development of a disease or
condition and are known in the art. An individual having one or more of
these risk factors has a higher probability of developing the disease or
condition than an individual without these risk factor(s).

[0062] "Nitroxyl" refers to the species HNO.

[0063] As used herein, a compound is a "nitroxyl donor" if it donates
nitroxyl under physiological conditions. As used herein, nitroxyl donors
of the invention may alternatively be referred to as "a compound" or "the
compound." Preferably, the nitroxyl donor is capable of donating an
effective amount of nitroxyl in vivo and has a safety profile indicating
the compound would be tolerated by an individual in the amount necessary
to achieve a therapeutic effect. One of ordinary skill in the art would
be able to determine the safety of administering particular compounds and
dosages to live subjects. One of skill in the art may also determine
whether a compound is a nitroxyl donor by evaluating whether it releases
HNO under physiological conditions. Compounds are easily tested for
nitroxyl donation with routine experiments. Although it is impractical to
directly measure whether nitroxyl is donated, several tests are accepted
for determining whether a compound donates nitroxyl. For example, the
compound of interest can be placed in solution, for example in water, in
a sealed container. After sufficient time for disassociation has elapsed,
such as from several minutes to several hours, the headspace gas is
withdrawn and analyzed to determine its composition, such as by gas
chromatography and/or mass spectroscopy. If the gas N2O is formed
(which occurs by HNO dimerization), the test is positive for nitroxyl
donation and the compound is a nitroxyl donor. The level of nitroxyl
donating ability may be expressed as a percentage of a compound's
theoretical maximum. A compound that donates a "significant level of
nitroxyl" intends a compound that donates 40% or more or 50% or more of
its theoretical maximum amount of nitroxyl. In one variation, the
compounds for use herein donate 60% or more of the theoretical maximum
amount of nitroxyl. In another variation, the compounds for use herein
donate 70% or more of the theoretical maximum amount of nitroxyl. In
another variation, the compounds for use herein donate 80% or more of the
theoretical maximum amount of nitroxyl. In another variation, the
compounds for use herein donate 90% or more of the theoretical maximum
amount of nitroxyl. In yet another variation, the compounds for use
herein donate between about 70% and about 90% of the theoretical maximum
amount of nitroxyl. In yet another variation, the compounds for use
herein donate between about 85% and about 95% of the theoretical maximum
amount of nitroxyl. In yet another variation, the compounds for use
herein donate between about 90% and about 95% of the theoretical maximum
amount of nitroxyl. Compounds that donate less than 40% or less than 50%
of their theoretical amount of nitroxyl are still nitroxyl donors and may
be used in the invention disclosed herein. A compound that donates less
than 50% of the theoretical amount of nitroxyl may be used in the methods
described, and may require higher dosing levels as compared to compounds
that donate a significant level of nitroxyl. Nitroxyl donation also can
be detected by exposing the test compound to metmyoglobin (Mb3+).
Nitroxyl reacts with Mb3+ to form an Mb2+--NO complex, which
can be detected by changes in the ultraviolet/visible spectrum or by
Electron Paramagnetic Resonance (EPR). The Mb2+--NO complex has an
EPR signal centered around a g-value of about 2. Nitric oxide, on the
other hand, reacts with Mb3+ to form an Mb3+--NO complex that
is EPR silent. Accordingly, if the candidate compound reacts with
Mb3+ to form a complex detectable by common methods such as
ultraviolet/visible or EPR, then the test is positive for nitroxyl
donation. Testing for nitroxyl donation may be performed at
physiologically relevant pH.

[0064] A "positive inotrope" as used herein is an agent that causes an
increase in myocardial contractile function. Such an agent includes a
beta-adrenergic receptor agonist, an inhibitor of phosphodiesterase
activity, and calcium-sensitizers. Beta-adrenergic receptor agonists
include, among others, dopamine, dobutamine, terbutaline, and
isoproterenol. Analogs and derivatives of such compounds are also
intended. For example, U.S. Pat. No. 4,663,351 describes a dobutamine
prodrug that can be administered orally. One of ordinary skill in the art
would be able to determine if a compound is capable of causing positive
inotropic effects and also additional beta-agonist compounds. In
particular embodiments, the beta-receptor agonist is selective for the
beta-1 receptor. However, in other embodiments the beta-agonist is
selective for the beta-2 receptor, or is not selective for any particular
receptor.

[0065] Diseases or conditions that are "responsive to nitroxyl therapy"
intends any disease or condition in which administration of a compound
that donates an effective amount of nitroxyl under physiological
conditions treats and/or prevents the disease or condition, as those
terms are defined herein. A disease or condition whose symptoms are
suppressed or diminished upon administration of nitroxyl donor is a
disease or condition responsive to nitroxyl therapy. Non-limiting
examples of diseases or conditions that are responsive to nitroxyl
therapy include coronary obstructions, coronary artery disease (CAD),
angina, heart attack, myocardial infarction, high blood pressure,
ischemic cardiomyopathy and infarction, diastolic heart failure,
pulmonary congestion, pulmonary edema, cardiac fibrosis, valvular heart
disease, pericardial disease, circulatory congestive states, peripheral
edema, ascites, Chagas' disease, ventricular hypertrophy, heart valve
disease, heart failure, including but not limited to congestive heart
failure such as acute congestive heart failure and acute decompensated
heart failure. Other cardiovascular diseases or conditions are also
intended, as are diseases or conditions that implicate
ischemia/reperfusion injury.

N-Hydroxysulfonamide Compounds

[0066] The compounds of this invention and for use in the methods
described herein include N-hydroxylsulfonamides that donate nitroxyl
under physiological conditions. Preferably, the compounds predominately
donate nitroxyl under physiological conditions, meaning that a compound
that donates both nitroxyl and nitric oxide under physiological
conditions donates more nitroxyl than nitric oxide. Preferably, the
compounds for use herein do not donate significant levels of nitric oxide
under physiological conditions. Most preferably, the compounds for use
herein donate significant levels of nitroxyl under physiological
conditions.

[0067] In one embodiment, the invention embraces a compound of the formula
(I):

[0069] In another embodiment, the compound is of the formula (I) where
R1 is H; R2 is H, aralkyl or heterocyclyl; R4, R5 and
R6 are independently H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl,
perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl,
substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl,
substituted heterocycloalkyl, dialkylamino, cycloalkoxy,
cycloalkylsulfanyl, arylsulfanyl, arylsulfinyl, carboxyl, carboxyl ester,
acylamino or sulfonylamino; at least one of R3 and R7 is an
electron withdrawing group or a group that sterically hinders the
sulfonyl moiety, provided that at least one of R3, R4, R5,
R6 and R7 is carboxyl, carboxyl ester, acylamino or
sulfonylamino. In one variation, at least one of R3 or R7 is an
electron withdrawing group. In another variation, both R3 and
R7 are electron withdrawing groups. In another variation, at least
one of R3 or R7 is a group that sterically hinders the sulfonyl
moiety of compound (I). In one variation, at least one of R3 or
R7 is a branched alkyl group, such as i-propyl or t-butyl. In
another variation, both R3 and R7 are alkyl groups provided
that one of the alkyl groups is a branched alkyl group, such as when both
groups are isopropyl or when one group is ethyl and the other is
sec-butyl. In one variation, one of R3 and R7 is an electron
withdrawing group and the R3 or R7 that is not an electron
withdrawing group is an alkyl group, which may be a branched alkyl group
such as isopropyl.

[0071] For any of the variations described for formula (I), included are
variations of formula (I) where R1 is H and R2 is H, benzyl or
tetrahydropyran-2-yl. In one variation, the compound is of the formula
(I) where at least two of R3, R4, R5, R6 and R7
are halo, such as the compound of formula (I) where R5 is halo (such
as F or Br) and one of R3 and R7 is halo (such as Br, or Cl) or
where both R3 and R7 or both R3 and R4 are halo (such
as when both are Cl or both are F or one is Cl and one is F), and the
remaining substituents are as described in the variations above. In one
variation, the compound is of the formula (I) where at least one of
R3, R4, R5, R6 and R7 is --S(O)2alkyl, such
as when one of R3 or R7 is --S(O)2CH3. In one
variation, the compound is of the formula (I) where at least one of
R3, R5 and R7 is a perhaloalkyl, such as when R3 is
CF3 or when R3 and R5 are CF3. In one variation, the
compound is of the formula (I) where R5 is CF3 and at least one
of R3 and R7 is other than H, such as when R5 is CF3
and R3 is NO2 or Cl. In one variation, the compound is of the
formula (I) where at least one of R3, R4, R5, R6 and
R7 is an aryl group, such as when at least one of R3 and
R7 is an aryl group, such as phenyl. In one variation, the compound
is of the formula (I) where at least one of R3, R4, R5,
R6 and R7 is a heterocyclyl group, such as when at least one of
R3, R5 and R7 is a heterocyclyl group or substituted
heterocylco group, such as morpholino, N-methyl, piperizino and
piperidino. In one variation, the compound is of the formula (I) where at
least one of R3, R4, R5, R6 and R7 is a
cycloalkoxy or cycloalkylsulfanyl group such as when at least one of
R3, R5 and R7 is a cyclohexyloxy, cyclopentyloxy,
cyclohexylsulfanyl or cyclopentylsulfanyl group. In one variation, the
compound is of the formula (I) where at least one of R3, R4,
R5, R6 and R7 is an arylsulfanyl or arylsulfinyl group,
such as when at least one of R3, R5 and R7 is a
phenylsulfanyl or phenylsulfinyl group.

[0072] For any of the variations described for formula (I), included are
variations of formula (I) where at least one of R3, R4,
R5, R6 and R7 is carboxyl. In one such variation, R4
is carboxyl, R3, R5 and R6 are H and R7 is H or halo.
In a particular variation, R4 is carboxyl, R3, R5 and
R6 are H, R7 is H or halo and R1 and R2 are H. For
any of the variations described for formula (I), included are variations
of formula (I) where at least one of R3, R4, R5, R6
and R7 is --COO-alkyl. In one such variation, R3 is --COO-alkyl
and R4, R5, R6 and R7 are H. In a particular
variation, R3 is --COO-alkyl, R4, R5, R6 and R7
are H and R1 and R2 are H. In another variation, R4 is
--COO-alkyl, one of R6 and R7 is --SR11, aryl,
--OR11, nitro, cyano, acyl, --S(O)2NHOH, sulfonylamino,
C1-C2perfluoroalkyl, lower alkyl or amino and the R6 or
R7 that is not SR11, aryl, --OR11, nitro, cyano, acyl,
--S(O)2NHOH, sulfonylamino, C1-C2perfluoroalkyl, lower
alkyl or amino is hydrogen. In another variation, R4 is --COO-alkyl,
one of R6 and R7 is --SR11, aryl, --OR11, nitro,
cyano, acyl, --S(O)2NHOH, sulfonylamino,
C1-C2perfluoroalkyl, lower alkyl or amino and the R6 or
R7 that is not --SR11, aryl, --OR11, nitro, cyano, acyl,
--S(O)2NHOH, sulfonamino, C1-C2perfluoroalkyl, lower alkyl
or amino is hydrogen, and R1, R2, R3 and R5 are
hydrogen. For any of the variations described for formula (I), included
are variations of formula (I) where at least one of R3, R4,
R5, R6 and R7 is --COO-substituted alkyl. In one such
variation, R4 is --COO-substituted alkyl, R3, R5 and
R6 are H and R7 is halo. In a particular variation, R4 is
--COO-substituted alkyl, R7 is halo, R3, R5 and R6
are H and R1 and R2 are H. For any of the variations described
for formula (I), included are variations of formula (I) where at least
one of R3, R4, R5, R6 and R7 is --C(O)NH2.
For any of the variations described for formula (I), included are
variations of formula (I) where at least one of R3, R4,
R5, R6 and R7 is --C(O) NRaRb where Ra is
hydrogen and Rb is alkyl. In one such variation, R4 is
--C(O)NRaRb where Ra is hydrogen, Rb is a lower
alkyl, R3, R5 and R6 are H and R7 is halo. In a
particular variation, R4 is --C(O)NRaRb where Ra is
hydrogen, Rb is lower alkyl, R3, R5 and R6 are H and
R7 is halo and R1 and R2 are H. In a particular variation,
Rb is a C2-C4 alkyl, such as ethyl, propyl or butyl. In
another variation, Rb is a branched lower alkyl, e.g., isopropyl or
isobutyl. For any of the variations described for formula (I), included
are variations of formula (I) where at least one of R3, R4,
R5, R6 and R7 is --C(O) NRaRb where Ra is
alkyl, substituted alkyl or hydrogen and Rb is substituted alkyl. In
one such variation, R4 is --C(O)NRaRb where Ra is
alkyl, substituted alkyl or hydrogen, Rb is substituted alkyl,
R3, R5 and R6 are H and R7 is halo. In a particular
variation, R4 is --C(O)NRaRb where Ra is alkyl,
substituted alkyl or hydrogen, Rb is substituted alkyl, R3,
R5 and R6 are H and R7 is halo and R1 and R2 are
H. In still another variation, R4 is --C(O)NRaRb where
Ra is lower alkyl, substituted lower alkyl or hydrogen, Rb is
substituted lower alkyl, R3, R5 and R6 are H and R7
is halo. When Rb is a substituted lower alkyl group, in one
variation it is a lower alkyl substituted with hydroxyl, carboxyl, amino
or alkoxy group. For example, the invention embraces compounds where
R4 is --C(O)NRaRb wherein Ra is hydrogen, methyl,
ethyl, or a lower alkyl substituted with hydroxyl or alkoxy group,
Rb is a lower alkyl substituted with hydroxyl, carboxyl, amino or
alkoxy group, R3, R5 and R6 are H and R7 is halo; in
a further variation R1 and R2 are H. For any of the variations
described for formula (I), included are variations of formula (I) where
at least one of R3, R4, R5, R6 and R7 is
--C(O)NRaRb where Ra and Rb are independently alkyl.
In one such variation, R4 is --C(O)NRaRb where Ra and
Rb are independently alkyl, R3, R5 and R6 are H and
R7 is halo. In another variation, R4 is --C(O)NRaRb
where Ra and Rb are independently alkyl, R3 and R5
are hydrogen and one of R6 and R7 is --SR11, aryl,
--OR11, nitro, cyano, acyl, --S(O)2NHOH, sulfonamino,
C1-C2perfluoroalkyl, lower alkyl or amino and the R6 or
R7 that is not --SR11, aryl, --OR11, nitro, cyano, acyl,
--S(O)2NHOH, sulfonamino, C1-C2perfluoroalkyl, lower alkyl
or amino is hydrogen. In a particular variation, R4 is
--C(O)NRaRb where Ra and Rb are independently alkyl,
R3, R5 and R6 are H and R7 is halo and R1 and
R2 are H. Ra and Rb may be the same or different, e.g.,
Ra and Rb in one variation are both methyl or ethyl. For any of
the variations described for formula (I), included are variations of
formula (I) where at least one of R3, R4, R5, R6 and
R7 is --C(O)NRaRb where Ra and Rb are taken
together with the nitrogen to which they are attached to form a
heterocyclic or substituted heterocyclic ring. In one such variation,
R4 is --C(O)NRaRb where Ra and Rb are taken
together with the nitrogen to which they are attached to form a
heterocyclic or substituted heterocyclic ring. In another variation,
R4 is --C(O)NRaRb where Ra and Rb are taken
together with the nitrogen to which they are attached to form a
heterocyclic or substituted heterocyclic ring, R3, R5 and
R6 are H and R7 is halo. In a particular variation, R4 is
--C(O)NRaRb where Ra and Rb are taken together with
the nitrogen to which they are attached to form a heterocyclic or
substituted heterocyclic ring, R3, R5 and R6 are H and
R7 is halo and R1 and R2 are H. In one variation, Ra
and Rb are taken together with the nitrogen to which they are
attached to form a heterocyclic ring, such as morpholino. In any
variation herein where R4 is --C(O)NRaRb, in a particular
variation, Ra and Rb are taken together with the nitrogen to
which they are attached to form a heterocyclic ring selected from
piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl and
morpholinyl. In any variation herein where R4 is
--(O)NRaRb, in a particular variation, Ra and Rb are
taken together with the nitrogen to which they are attached to form a
heterocyclic ring substituted with 1 or 2 moieties selected from lower
alkyl, carboxylester, acyl, halo, amino, hydroxyl, substituted lower
alkyl, oxo and alkoxy. For example, in any variation herein where R4
is --C(O)NRaRb, in a particular variation, Ra and Rb
are taken together with the nitrogen to which they are attached to form a
substituted heterocyclic ring selected from 2,6-dimethylpiperaz-4-yl,
1-isopropylpiperaz-4-yl, 1-(piperazin-4-yl)ethanone, tert-butyl
piperaz-4-yl-1-carboxylate, 4-fluoropiperidyl, 4,4-difluoropiperidyl,
4-aminopiperidyl, 4-hydroxypiperidyl, 4-oxopiperidinyl,
4-methoxypiperidyl, 4-(2-hydroxyethyl)piperidyl,
2-(piperid-4-yl)-ethoxyethanol, 3-hydroxy-azetidinyl,
2-oxo-piperazin-4-yl and 1-methyl-2-oxo-piperazin-4-yl. For any of the
variations described for formula (I), included are variations of formula
(I) where at least one of R3, R4, R5, R6 and R7
is --SO2NH2. For any of the variations described for formula
(I), included are variations of formula (I) where at least one of
R3, R4, R5, R6 and R7 is --SO2NR-alkyl
where R is hydrogen. For any of the variations described for formula (I),
included are variations of formula (I) where at least one of R3,
R4, R5, R6 and R7 is --SO2NR-alkyl where R is
alkyl. In a particular variation, R4 is --SO2NR-alkyl where R
is alkyl and R3, R5, R6 and R7 are hydrogen. For
example, in one variation, R4 is --SO2N(lower alkyl)2 and
R3, R5, R6 and R7 are hydrogen, where the lower alkyl
substituents may be the same or different, e.g., R4 may be
--SO2N(Et)2 or --SO2N(Et)(Me). For any of the variations
described for formula (I), included are variations of formula (I) where
at least one of R3, R4, R5, R6 and R7 is
--SO2NR2, where the two R groups are taken together with the
nitrogen to which they are attached to form a heterocyclic or substituted
heterocyclic ring. In one such variation, R3 is --SO2NR2,
where the two R groups are taken together with the nitrogen to which they
are attached to form a heterocyclic or substituted heterocyclic ring. In
another variation, R3 is --SO2NR2, where the two R groups
are taken together with the nitrogen to which they are attached to form a
heterocyclic or substituted heterocyclic ring and R4, R5,
R6 and R7 are H. In a particular variation, R3 is
--SO2NR2, where the two R groups are taken together with the
nitrogen to which they are attached to form a heterocyclic or substituted
heterocyclic ring and R4, R5, R6 and R7 are H and
R1 and R2 are H. In one variation, at least one of R3,
R4, R5, R6 and R7 is --SO2NR2, where the
two R groups are taken together with the nitrogen to which they are
attached to form a heterocyclic ring, such as a morpholino ring.

[0073] Representative compounds of the formula (I) include, but are not
limited to, the compounds listed in Table 1.

[0074] In one embodiment, the nitroxyl donating compound is a compound of
the formula (IIa):

##STR00075##

where R1 is H; R2 is H, aralkyl or heterocyclyl; m and n are
independently an integer from 0 to 1; x is an integer from 0 to 4 and y
is an integer from 0 to 3, provided that at least one of x and y is
greater than 0; A is a cycloalkyl, heterocycloalkyl, aromatic or
heteroaromatic ring containing ring moieties Q1, Q2, Q3
and Q4, which are taken together with the carbons at positions a and
a' to form ring A; B is a cycloalkyl, heterocycloalkyl, aromatic or
heteroaromatic ring containing ring moieties Q5, Q6, Q7
and Q8, which are taken together with the carbons at positions a and
a' to form ring B; Q1, Q2, Q3, Q4, Q5, Q6,
Q7and Q8 are independently selected from the group consisting
of C, CH2, CH, N, NR10, O and S; each R8 and R9 is
independently selected from the group consisting of halo, alkylsulfonyl,
N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy,
perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl,
heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, NH2,
OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH2,
NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH2,
OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N--OH)NH2, cycloalkoxy,
cycloalkylsulfanyl, arylsulfanyl, arylsulfinyl, carbonylamino and
sulfonylamino, provided that at least one R8 is carbonylamino or
sulfonylamino; and, R10 is H, alkyl, acyl, or sulfonyl.

[0075] In one variation, the compound is of the formula (II) or (IIa)
where each R8 and R9 is independently selected from the group
consisting of Cl, F, I, Br, SO2CH3, SO2NHOH, CF3,
CH3, NO2, phenyl, CN, OCH3, OCF3, t-Bu, O-iPr,
4-nitrophenyloxy (OPh4-NO2), propane-2-thiyl (SCH(CH3)2),
propane-2-sulfinyl (S(O)CH(CH3)2), morpholino,
N-methyl-piperazino, dimethylamino, piperidino, cyclohexyloxy,
cyclopentylsulfanyl, phenylsulfanyl, phenylsulfinyl, carbonylamino and
sulfonylamino, provided that at least one R8 is carbonylamino or
sulfonylamino; and R10 is H, alkyl, acyl or sulfonyl, provided that
when rings A and B form naphthalene, x is an integer from 1 to 3 or y is
an integer from 2 to 4.

[0076] For any of the variations described for formula (II) or (IIa),
included are variations of formula (II) or (IIa) where R1 is H and
R2 is H, benzyl or tetrahydropyran-2-yl. In one variation, A and B
form a benzofuran or benzothiophene or benzoimidazole or
N-alkylbenzoimidazole (such as N-methylbenzoimidazole) or
N-acylbenzoimidazole (such as N--C(O)CH3benzoimidazole) or
benzothiazole or benzooxazole. In one variation, A and B are other than
napthyl or quinoline. In one variation, A and B are napthyl or quinoline.
In one variation, A and B form a benzofuran. In one variation, A and B
form a benzofuran. In one variation, A and B form a benzothiophene. In
one variation, A and B form a benzothiophene, y is 0 and x is 1. In one
variation, A and B form naphthyl and x is 0, y is 1. In one variation,
ring A is phenyl and ring B is a heteroaryl group, such as when rings A
and B form quinoline and ring B is the nitrogen containing ring. The
invention also embraces compounds according to any of the variations for
formula (II) or (IIa) where y is 0, x is 1 and R9 is a halo, alkyl
or perhaloalkyl group. The invention also embraces compounds according to
any of the variations for formula (II) or (IIa) where x is 2 and y is 0.

[0077] For any of the variations described for formula (II) or (IIa),
included are variations of formula (II) or (IIa) where at least one of
R8 and R9 is --CONH-alkyl. For any of the variations described
for formula (II) or (Ha), included are variations of formula (II) or
(IIa) where at least one of R8 and R9 is --CONR-alkyl where R
is alkyl. For any of the variations described for formula (II) or (IIa),
included are variations of formula (II) or (IIa) where at least one of
R8 and R9 is --CONR2 where each R is independently alkyl.
In a particular variation of formula (II) or (IIa), y is 0, x is 1 and
R9 is --CONR2 where each R is independently alkyl. In another
variation of formula (II) or (IIa), y is 0, x is 1 and R9 is
--CONR2 where each R is independently lower alkyl, where each lower
alkyl can be the same (e.g., --CON(Me)2) or different. For any of
the variations described for formula (II) or (IIa), included are
variations of formula (II) or (IIa) where at least one of R8 and
R9 is --CONR2 where each R taken together with the nitrogen to
which it is attached to form a heterocylic or substituted heterocyclic
ring. For any of the variations described for formula (II) or (IIa),
included are variations of formula (II) or (IIa) where at least one of
R8 and R9 is --CONR2 where each R is independently alkyl.
For any of the variations described for formula (II) or (IIa), included
are variations of formula (II) or (IIa) where at least one of R8 and
R9 is --NRaSO2NR-alkyl where Ra and R are
independently hydrogen or alkyl. For any of the variations described for
formula (II) or (IIa), included are variations of formula (II) or (IIa)
where at least one of R8 and R9 is --SO2NH2. For any
of the variations described for formula (II) or (IIa), included are
variations of formula (II) or (IIa) where at least one of R8 and
R9 is --SO2NH2. For any of the variations described for
formula (II) or (IIa), included are variations of formula (II) or (IIa)
where at least one of R8 and R9 is --SO2NR-alkyl, where R
is hydrogen or alkyl. For any of the variations described for formula
(II) or (IIa), included are variations of formula (II) or (IIa) where at
least one of R8 and R9 is --SO2NR2, where the two R
groups are taken together and with the nitrogen atom to which they are
attached to form a heterocyclic or substituted heterocyclic ring. In a
particular variation of formula (II) or (IIa), y is 0, x is 1 and R9
is --SO2NR2, where the two R groups are taken together and with
the nitrogen atom to which they are attached to form a heterocyclic ring.
In another variation of formula (II) or (IIa), y is 0, x is 1 and R9
is --SO2NR2, where the two R groups are taken together and with
the nitrogen atom to which they are attached to form a morpholino group.

[0078] Representative compounds of the formula (IIa) include, but are not
limited to, the compounds listed in Table 2.

[0079] In another embodiment, the nitroxyl donating compound is a compound
of the formula (III):

##STR00080##

[0080] where R1 is H; R2 is H, aralkyl or heterocyclyl; n is an
integer from 0 to 1; b is an integer froml to 4; C is a heteroaromatic
ring containing ring moieties Q9, Q10, Q11, Q12,
Q13 and Q14 that are independently selected from the group
consisting of C, CH2, CH, N, NR10, O and S, provided that at
least one of Q9, Q10, Q11, Q12, Q13 and Q14
is N, NR10, O or S; each R8 is independently selected from the
group consisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl,
perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl,
substituted aryloxy, alkylsulfanyl, heterocycloalkyl, substituted
heterocycloalkyl, dialkylamino, NH2, OH, C(O)OH, C(O)Oalkyl,
NHC(O)alkylC(O)OH, C(O)NH2, NHC(O)alkylC(O)alkyl,
NHC(O)alkenylC(O)OH, NHC(O)NH2, OalkylC(O)Oalkyl, NHC(O)alkyl,
C(═N--OH)NH2, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl,
arylsulfinyl, carbonylamino or sulfonylamino, provided that at least one
R8 is carbonylamino or sulfonylamino; and R10 is H, alkyl, acyl
or sulfonyl.

[0081] In one variation, the compound is of the formula (III) and each
R8 is independently selected from the group consisting of Cl, F, I,
Br, SO2CH3, SO2NHOH, CF3, CH3, NO2, phenyl,
CN, OCH3, OCF3, t-Bu, O-iPr, 4-nitrophenyloxy (OPh4-NO2),
propane-2-thiyl (SCH(CH3)2), propane-2-sulfinyl
(S(O)CH(CH3)2), morpholino, N-methyl-piperazino, dimethylamino,
piperidino, cyclohexyloxy, cyclopentylsulfanyl, phenylsulfanyl,
phenylsulfinyl, carbonylamino or sulfonylamino, provided that at least
one R8 is carbonylamino or sulfonylamino. In another variation, the
compound is of the formula (III) and each R8 is independently
selected from the group consisting of F, Br, Cl, CF3, phenyl,
methyl, SO2NHOH, morpholino, piperidino, 4-methyl-piperazino,
carbonylamino and sulfonylamino, provided that at least one R8 is
carbonylamino or sulfonylamino.

[0082] For any of the variations described for formula (III), included are
variations of formula (III) where R1 is H and R2 is H, benzyl
or tetrahydropyran-2-yl. In one variation, n is 0 and C is a thiophene or
isoxazole or pyrazole or pyrrole or imidazole or furan or thiazole or
triazole or N-methylimidazole or thiadiazole. In one variation, C is
other than thienyl. In another variation, n is 0 and C is a thiophene or
isoxazole or pyrazole or pyrrole or imidazole or furan or thiazole or
triazole or N-methylimidazole or thiadiazole. In one variation, n is 1
and C is a pyrimidine or pyrazine or pyridine. In one variation, n is 1
and C is a pyrimidine or pyrazine or pyridine and b is 1. In one
variation, n is 1 and C is a pyrimidine or pyrazine or pyridine, b is 1,
and at least one R8 is chloro or morpholino or piperidino or
N-methylpiperizino. In one variation, C is thiophene and b is 1. In one
variation, C is thiophene, b is 1 and at least one R8 is halo. In
one variation, C is thiophene.

[0083] For any of the variations described for formula (III), included are
variations of formula (III) where at least one R8 is --CONH2.
In one variation, C is a thiophene substituted with --CONH2, and
optionally substituted with an additional R8, such as an amino
group. For any of the variations described for formula (III), included
are variations of formula (III) where at least one R8 is
--CONH-alkyl. For example, compounds wherein R8 is --CONH-lower
alkyl (e.g., isopropyl) are encompassed.For any of the variations
described for formula (III), included are variations of formula (III)
where at least one R8 is --CONH-substituted alkyl. In a particular
variation, C is thiophene, R1 and R2 are both H and at least
one R8 is --CONH-substituted alkyl. For any of the variations
described for formula (III), included are variations of formula (III)
where at least one R8 is --CONR-alkyl where R is alkyl. For any of
the variations described for formula (III), included are variations of
formula (III) where at least one R8 is --CONR2 where each R is
independently alkyl, such as --CON(Me)2. In a particular variation,
C is a thiophene, b is 2, one of R8 is --CONR2 where each R is
independently alkyl (such as --CON(Me)2) and the other R8 is
--S(O)2Alkyl, aryl, heteroaryl, or --S-alkyl. For any of the
variations described for formula (III), included are variations of
formula (III) where at least one R8 is --CONR2 where each R is
independently a substituted alkyl, such as
--CH2CH2OCH3.For any of the variations described for
formula (III), included are variations of formula (III) where at least
one R8 is --CONR2 where each R taken together with the nitrogen
to which it is attached to form a heterocylic or substituted heterocyclic
ring. In a particular variation, C is thiophene, R1 and R2 are
both H and at least one R8 is --CONR2 where each R taken
together with the nitrogen to which it is attached to form a heterocylic
or substituted heterocyclic ring, such as morpholino. In a another
variation, C is thiophene, R1 and R2 are both H, b is 1 or 2,
at least one R8 is --CONR2 where each R taken together with the
nitrogen to which it is attached to form a heterocylic ring selected from
piperidinyl and morpholinyl and when b is 2, the R8 that is other
than is --CONR2 is selected from halo, nitro and --OR11, such
as --Oalkyl (e.g., methoxy). In a another variation, C is thiophene,
R1 and R2 are both H, b is 1 or 2, at least one R8 is
--CONR2 where each R taken together with the nitrogen to which it is
attached to form a heterocyclic ring substituted with 1 or 2 moieties
selected from lower alkyl, carboxylester, acyl, halo, amino, hydroxyl,
substituted lower alkyl, oxo and alkoxy. For example, in any variation
herein where R8 is --CONR2 where each R taken together with the
nitrogen to which it is attached to form a substituted heterocyclic ring
selected from 1-methyl-piperaz-4-yl, 4-fluoropiperidyl and
4-hydroxypiperidyl. For any variation, e.g., when C is thiophene
substituted with R8 is --CONR2, C may also be substituted with
a moiety selected from halo, amino, hydroxyl, alkoxy, nitro and cyano.For
any of the variations described for formula (III), included are
variations of formula (III) where at least one R8 is --CONR2
where each R is independently alkyl. For any of the variations described
for formula (III), included are variations of formula (III) where at
least one R8 is --NRaSO2NR-alkyl where Ra and R are
independently hydrogen or alkyl. For any of the variations described for
formula (III), included are variations of formula (III) where at least
one R8 is --SO2NH2. For any of the variations described
for formula (III), included are variations of formula (III) where at
least one R8 is --SO2NH2 For any of the variations
described for formula (III), included are variations of formula (III)
where at least one R8 is --SO2NR-alkyl, where R is hydrogen or
alkyl. For any of the variations described for formula (III), included
are variations of formula (III) where at least one R8 is
--SO2NR2, where the two R groups are taken together and with
the nitrogen atom to which they are attached to form a heterocyclic or
substituted heterocyclic ring.

[0084] Representative compounds of the formula (III) include, but are not
limited to, the compounds listed in Table 3.

[0085] The methods described employ compounds of the invention that donate
an effective amount of nitroxyl under physiological conditions. Any of
the methods may employ an N-hydroxylsulfonamide compound described above
under "N-Hydroxysulfonamide Compounds."

[0086] For any of the compounds of the invention, such as the compounds of
formula (I), (II) or (III) or other compounds for use in the methods
described herein, recitation or depiction of the parent compound intends
and includes all salts, solvates, hydrates, polymorphs, or prodrugs
thereof, where applicable. As such, all salts, such as pharmaceutically
acceptable salts, solvates, hydrates, polymorphs and prodrugs of a
compound are embraced by the invention and described herein the same as
if each and every salts, solvate, hydrate, polymorph, or prodrug were
specifically and individually listed.

[0087] For all compounds disclosed herein, where applicable due to the
presence of a stereocenter, the compound is intended to embrace all
possible stereoisomers of the compound depicted or described.
Compositions comprising a compound with at least one stereocenter are
also embraced by the invention, and includes racemic mixtures or mixtures
containing an enantiomeric excess of one enantiomer or single
diastereomers or diastereomeric mixtures. All such isomeric forms of
these compounds are expressly included herein the same as if each and
every isomeric form were specifically and individually listed. The
compounds herein may also contain linkages (e.g., carbon-carbon bonds)
wherein bond rotation is restricted about that particular linkage, e.g.
restriction resulting from the presence of a ring or double bond.
Accordingly, all cis/trans and E/Z isomers are also expressly included in
the present invention. The compounds herein may also be represented in
multiple tautomeric forms, in such instances, the invention expressly
includes all tautomeric forms of the compounds described herein, even
though only a single tautomeric form may be represented. Also embraced
are compositions of substantially pure compound. A composition of
substantially pure compound means that the composition contains no more
than 25%, or no more than 15%, or no more than 10%, or no more than 5%,
or no more than 3% impurity, or no more than 1% impurity, such as a
different biologically active compound, which may include a different
stereochemical form of the compound if the composition contains a
substantially pure single isomer.

[0088] The compounds of the invention can be made according to the general
methods described in Schemes A-D or by procedures known in the art.
Starting materials for the reactions are either commercially available or
may be prepare by known procedures or obvious modifications thereof. For
example, many of the starting materials are available from commercial
suppliers such as Sigma-Aldrich. Others may be prepared by procedures or
obvious modifications thereof described in standard reference texts such
as March's Advanced Organic Chemistry, (John Wiley and Sons) and Larock's
Comprehensive Organic Transformations (VCH Publishers Inc.).

##STR00103##

[0089] In Scheme A, a solution of hydroxylamine hydrochloride in water is
chilled to 0° C. A solution of potassium carbonate in water is
added dropwise, maintaining an internal reaction temperature between
about 5° C. and about 15° C. The reaction mixture is
stirred for about 15 minutes, whereupon tetrahydrofuran (THF) and
methanol (MeOH) are added. Compound A1 (where R is an alkyl, aryl or
heterocyclyl group) is added portionwise maintaining a temperature below
about 15° C. and the reaction mixture is stirred at ambient
temperature until complete consumption of the sulfonyl chloride is
observed by thin layer chromatography (TLC). The resulting suspension is
concentrated to remove any volatiles and the aqueous suspension is
extracted with diethyl ether. The organic portion is dried over magnesium
sulfate, filtered and concentrated in vacuo to yield the crude N-hydroxy
sulphonamide A2. Purification may be achieved by conventional methods,
such as chromatography, filtration, crystallization and the like.

##STR00104##

[0090] In Scheme B, a solution of aqueous hydroxylamine in water and THF
is chilled to -5° C. Compound A1 (where R is an alkyl, aryl or
heterocyclyl group) is added portionwise maintaining a temperature below
about 10° C. and the reaction mixture is stirred at ambient
temperature until complete consumption of the sulfonyl chloride is
observed by thin layer chromatography (TLC). The resulting suspension is
concentrated to remove any volatiles and the aqueous suspension is
extracted with diethyl ether. The organic portion is dried over magnesium
sulfate, filtered and concentrated in vacuo to yield the crude N-hydroxy
sulphonamide A2. Purification may be achieved by conventional methods,
such as chromatography, filtration, crystallization and the like.

##STR00105##

[0091] N-Benzyloxysulfonamides are chemical intermediates that are used as
protected N-hydroxysulfonamides for the further modification of the R
moiety of compound B2. In Scheme B, a suspension of O-benzylhydroxylamine
hydrochloride B1 in methanol and water is added to a chilled solution of
potassium carbonate in water, maintaining an internal reaction
temperature below about 10° C. The reaction mixture is stirred for
about 5 minutes, whereupon THF and A1 (where R is an alkyl, aryl or
heterocyclyl group) are added. The reaction mixture is stirred at ambient
temperature until complete consumption of the sulfonyl chloride was
observed by TLC. The resulting suspension is concentrated in vacuo to
remove any volatiles, and the aqueous suspension was extracted with
diethyl ether. The organic layer was dried over sodium sulfate, filtered
and concentrated in vacuo to yield the crude target compound B2.
Purification may be achieved by conventional methods, such as
chromatography, filtration, crystallization and the like. The reaction
product B2 may be deprotected by removing the benzyl group. For instance,
a suspension of 10% palladium on charcoal may be added to a suspension of
B2 in methanol. The reaction mixture is stirred under a hydrogen
atmosphere at ambient temperature and atmospheric pressure overnight. The
reaction mixture is filtered through microfibre glass paper. The
resulting filtrate is concentrated in vacuo, and the residue purified by
conventional methods to yield the corresponding N-hydroxylsulfonamide.

##STR00106##

[0092] N-(tetrahydro-pyran-2-yloxy)sulfonamides are chemical intermediates
that are used as protected N-hydroxysulfonamides for the further
modification of the R moiety of compound C2. In Scheme C, to a solution
of C1 in water at 0° C. is added a solution of potassium carbonate
in water dropwise, maintaining an internal reaction temperature below
about 10° C. After about 15 minutes, methanol and THF are added
dropwise, followed by A1 portionwise. The reaction mixture is stirred at
ambient temperature until complete consumption of the sulfonyl chloride
is observed by TLC. The resulting suspension was concentrated to remove
any volatiles and the aqueous suspension was extracted with diethyl
ether. The organic portion is dried over sodium sulfate, filtered and
concentrated in vacuo to yield the crude target compound C2. Purification
may be achieved by conventional methods, such as chromatography,
filtration, crystallization and the like. Deprotection of C2 to yield the
corresponding N-hydroxylsulfonamide may be carried out according to
methods known in the art.

Methods of Using the Compounds and Compositions

[0093] The compounds and compositions herein may be used to treat and/or
prevent the onset and/or development of a disease or condition that is
responsive to nitroxyl therapy.

[0094] The invention embraces methods of administering to an individual
(including an individual identified as in need of such treatment) an
effective amount of a compound to produce a desired effect. Identifying a
subject in need of such treatment can be in the judgment of a physician,
clinical staff, emergency response personnel or other health care
professional and can be subjective (e.g. opinion) or objective (e.g.
measurable by a test or diagnostic method).

[0095] One embodiment provides a method of modulating (including
increasing) in vivo nitroxyl levels in an individual in need thereof, the
method comprising administering to the individual a compound that donates
nitroxyl under physiological conditions or a pharmaceutically acceptable
salt thereof An individual is in need of nitroxyl modulation if they have
or are suspected of having or are at risk of having or developing a
disease or condition that is responsive to nitroxyl therapy.

[0096] Particular diseases or conditions embraced by the methods of the
invention include cardiovascular diseases such as heart failure or
conditions and diseases or conditions that implicate or may implicate
ischemia/reperfusion injury. These methods are described in more detail
below.

[0097] Compositions comprising a nitroxyl-donating compound of the
invention are embraced by the invention. However, the methods described
may use more than one nitroxyl donating compound; for example, the
methods may employ Angeli's salt and an N-hydroxysulfonamide of the
present invention or two or more N-hydroxysulfonamides of the present
invention, which may be administered together or sequentially.

Cardiovascular Diseases

[0098] Provided herein are methods of treating cardiovascular diseases
such as heart failure by administering an effective amount of at least
one nitroxyl donating compound to an individual in need thereof Also
provided are methods of administering a therapeutically effective dose of
at least one nitroxyl donating compound in combination with at least one
other positive inotropic agent to an individual in need thereof Further
provided are methods of administering a therapeutically effective amount
of at least one nitroxyl donating compound to an individual who is
receiving beta-antagonist therapy and who is experiencing heart failure.
Methods are provided herein for administering compounds of the invention
in combination with beta-adrenergic agonists to treat heart failure. Such
agonists include dopamine, dobutamine, and isoproterenol, and analogs and
derivatives of such compounds. Also provided are methods of administering
nitroxyl donors to individuals receiving treatment with beta-antagonizing
agents such as propranolol, metoprolol, bisoprolol, bucindolol, and
carvedilol. Further, methods are provided herein for treating specific
classifications of heart failure, such as Class III heart failure and
acute heart failure.

[0099] Also embraced by the invention is a method of treating congestive
heart failure (CHF), including acute congestive heart failure, by
administering an effective amount at least one nitroxyl donating compound
to an individual in need thereof, which individual may be experiencing
heart failure. Also disclosed is a method of treating CHF by
administering an effective amount of at least one nitroxyl donating
compound in combination with an effective amount of at least one other
positive inotropic agent to an individual in need thereof, which
individual may be experiencing heart failure. In one variation, the other
positive inotrope is a beta-adrenergic agonist, such as dobutamine. The
combined administration of a nitroxyl donor and at least one other
positive inotropic agent comprises administering the nitroxyl donor
either sequentially with the other positive inotropic agent for example,
the treatment with one agent first and then the second agent, or
administering both agents at substantially the same time, wherein there
is an overlap in performing the administration. With sequential
administration, an individual is exposed to the agents at different
times, so long as some amount of the first agent, which is sufficient to
be therapeutically effective in combination with the second agent,
remains in the subject when the other agent is administered. Treatment
with both agents at the same time can involve administration of the
agents in the same dose, such as a physically mixed dose, or in separate
doses administered at the same time.

[0100] In particular an embodiment, a nitroxyl donor is administered to an
individual experiencing heart failure that is receiving beta-antagonist
therapy. A beta-antagonist (also known as a beta-blocker) includes any
compound that effectively acts as an antagonist at a subject's
beta-adrenergic receptors, and provides desired therapeutic or
pharmaceutical results, such as diminished vascular tone and/or heart
rate. A subject who is receiving beta-antagonist therapy is any subject
to whom a beta-antagonist has been administered, and in whom the
beta-antagonist continues to act as an antagonist at the subject's
beta-adrenergic receptors. In particular embodiments a determination of
whether a subject is receiving beta-blocking therapy is made by
examination of the subject's medical history. In other embodiments the
subject is screened for the presence of beta-blocking agents by chemical
tests, such as high-speed liquid chromatography as described in Thevis et
al., Biomed. Chromatogr., 15:393-402 (2001).

[0101] The administration of a nitroxyl donating compound either alone, in
combination with a positive inotropic agent, or to a subject receiving
beta-antagonist therapy, is used to treat heart failure of all
classifications. In particular embodiments a nitroxyl donating compound
is used to treat early-stage chronic heart failure, such as Class II
heart failure. In other embodiments a nitroxyl donating compound is used
in combination with a positive inotropic agent, such as isoproterenol to
treat Class IV heart failure. In still other embodiments a nitroxyl
donating compound is used in combination with another positive inotropic
agent, such as isoproterenol to treat acute heart failure. In some
embodiments, when a nitroxyl donor is used to treat early stage heart
failure, the dose administered is lower than that used to treat acute
heart failure. In other embodiments the dose is the same as is used to
treat acute heart failure.

Ischemia/Reperfusion Injury

[0102] The invention embraces methods of treating or preventing or
protecting against ischemia/reperfusion injury. In particular, compounds
of the invention are beneficial for individuals at risk for an ischemic
event. Thus, provided herein is a method of preventing or reducing the
injury associated with ischemia/reperfusion by administering an effective
amount of at least one nitroxyl donating compound to an individual,
preferably prior to the onset of ischemia. A compound of the invention
may be administered to an individual after ischemia but before
reperfusion. A compound of the invention may also be administered after
ischemia/reperfusion, but where the administration protects against
further injury. Also provided is a method in which the individual is
demonstrated to be at risk for an ischemic event. Also disclosed is a
method of administering a nitroxyl donating compound to an organ that is
to be transplanted in an amount effective to reduce ischemia/reperfusion
injury to the tissues of the organ upon reperfusion in the recipient of
the transplanted organ.

[0103] Nitroxyl donors of the invention may thus be used in methods of
preventing or reducing injury associated with future
ischemia/reperfusion. For example, administration of a nitroxyl donor
prior to the onset of ischemia may reduce tissue necrosis (the size of
infarct) in at-risk tissues. In live subjects this may be accomplished by
administering an effective amount of a nitroxyl donating compound to an
individual prior to the onset of ischemia. In organs to be transplanted
this is accomplished by contacting the organ with a nitroxyl donor prior
to reperfusion of the organ in the transplant recipient. Compositions
comprising more than one nitroxyl-donating compound also could be used in
the methods described, for example, Angeli's salt and an
N-hydroxysulfonamide of the present invention or two or more
N-hydroxysulfonamides of the present invention. The nitroxyl-donating
compound also can be used in combination with other classes of
therapeutic agents that are designed to minimize ischemic injury, such as
beta blockers, calcium channel blockers, anti-platelet therapy or other
interventions for protecting the myocardium in individuals with coronary
artery disease.

[0104] One method of administering a nitroxyl donor to live subjects
includes administration of the nitroxyl-donating compound prior to the
onset of ischemia. This refers only to the onset of each instance of
ischemia and would not preclude performance of the method with subjects
who have had prior ischemic events, i.e., the method also contemplates
administration of nitroxyl-donating compounds to a subject who has had an
ischemic event in the past.

[0105] Individuals can be selected who are at risk of a first or
subsequent ischemic event. Examples include individuals with known
hypercholesterolemia, EKG changes associated with risk of ischemia,
sedentary lifestyle, angiographic evidence of partial coronary artery
obstruction, echocardiographic evidence of myocardial damage, or any
other evidence of a risk for a future or additional ischemic event (for
example a myocardial ischemic event, such as a myocardial infarction
(MI), or a neurovascular ischemia such as a cerebrovascular accident
CVA). In particular examples of the methods, individuals are selected for
treatment who are at risk of future ischemia, but who have no present
evidence of ischemia (such as electrocardiographic changes associated
with ischemia (for example, peaked or inverted T-waves or ST segment
elevations or depression in an appropriate clinical context), elevated
CKMB, or clinical evidence of ischemia such as crushing sub-sternal chest
pain or arm pain, shortness of breath and/or diaphoresis). The
nitroxyl-donating compound also could be administered prior to procedures
in which myocardial ischemia may occur, for example an angioplasty or
surgery (such as a coronary artery bypass graft surgery). Also embraced
is a method of administering a nitroxyl-donating compound to an
individual at demonstrated risk for an ischemic event. The selection of
an individual with such a status could be performed by a variety of
methods, some of which are noted above. For example, an individual with
one of more of an abnormal EKG not associated with active ischemia, prior
history of myocardial infarction, elevated serum cholesterol, etc., would
be at risk for an ischemic event. Thus, an at-risk individual could be
selected by physical testing or eliciting the potential subject's medical
history to determine whether the subject has any indications of risk for
an ischemic event. If risk is demonstrated based on the indications
discussed above, or any other indications that one skilled in the art
would appreciate, then the individual would be considered at demonstrated
risk for an ischemic event.

[0106] Ischemia/reperfusion may damage tissues other than those of the
myocardium and the invention embraces methods of treating or preventing
such damage. In one variation, the method finds use in reducing injury
from ishemia/reperfusion in the tissue of the brain, liver, gut, kidney,
bowel, or in any other tissue. The methods preferably involve
administration of a nitroxyl donor to an individual at risk for such
injury. Selecting a person at risk for non-myocardial ischemia could
include a determination of the indicators used to assess risk for
myocardial ischemia. However, other factors may indicate a risk for
ischemia/reperfusion in other tissues. For example, surgery patients
often experience surgery related ischemia. Thus, individuals scheduled
for surgery could be considered at risk for an ischemic event. The
following risk factors for stroke (or a subset of these risk factors)
would demonstrate a subject's risk for ischemia of brain tissue:
hypertension, cigarette smoking, carotid artery stenosis, physical
inactivity, diabetes mellitus, hyperlipidemia, transient ischemic attack,
atrial fibrillation, coronary artery disease, congestive heart failure,
past myocardial infarction, left ventricular dysfunction with mural
thrombus, and mitral stenosis. Ingall, "Preventing ischemic stroke:
current approaches to primary and secondary prevention," Postgrad. Med.,
107(6):34-50 (2000). Further, complications of untreated infectious
diarrhea in the elderly can include myocardial, renal, cerebrovascular
and intestinal ischemia. Slotwiner-Nie & Brandt, "Infectious diarrhea in
the elderly," Gastroenterol, Clin. N. Am., 30(3):625-635 (2001).
Alternatively, individuals could be selected based on risk factors for
ischemic bowel, kidney or liver disease. For example, treatment would be
initiated in elderly subjects at risk of hypotensive episodes (such as
surgical blood loss). Thus, subjects presenting with such an indication
would be considered at risk for an ischemic event. Also embraced is a
method of administering a nitroxyl donating compound of the invention to
an individual who has any one or more of the conditions listed herein,
such as diabetes mellitus or hypertension. Other conditions that may
result in ischemia such as cerebral arteriovenous malformation would be
considered to demonstrate risk for an ischemic event.

[0107] The method of administering nitroxyl to organs to be transplanted
includes administration of nitroxyl prior to removal of the organ from
the donor, for example through the perfusion cannulas used in the organ
removal process. If the organ donor is a live donor, for example a kidney
donor, the nitroxyl donor can be administered to the organ donor as
described above for a subject at risk for an ischemic event. In other
cases the nitroxyl donor can be administered by storing the organ in a
solution comprising the nitroxyl donor. For example, the nitroxyl donor
can be included in the organ preservation solution, such as University of
Wisconsin "UW" solution, which is a solution comprising hydroxyethyl
starch substantially free of ethylene glycol, ethylene chlorohydrin and
acetone (see U.S. Pat. No. 4,798,824).

Pharmaceutical Composition, Dosage Forms and Treatment Regimens

[0108] Also included are pharmaceutically acceptable compositions
comprising a compound of the invention or pharmaceutically acceptable
salt thereof and any of the methods may employ the compounds of the
invention as a pharmaceutically acceptable composition. A
pharmaceutically acceptable composition includes one or more of the
compounds of the invention together with a pharmaceutically acceptable
carrier. The pharmaceutical compositions of the invention include those
suitable for oral, rectal, nasal, topical (including buccal and
sublingual), vaginal or parenteral (including subcutaneous,
intramuscular, intravenous and intradermal) administration.

[0109] The compounds or compositions may be prepared as any available
dosage form. Unit dosage forms are also intended, which includes discrete
units of the compound or composition such as capsules, sachets or tablets
each containing a predetermined amount of the compound; as a powder or
granules; as a solution or a suspension in an aqueous liquid or a
non-aqueous liquid; or as an oil-in-water liquid emulsion or a
water-in-oil liquid emulsion, or packed in liposomes and as a bolus, etc.

[0110] A tablet containing the compound or composition may be made by
compression or molding, optionally with one or more accessory
ingredients. Compressed tablets may be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form such as a
powder or granules, optionally mixed with a binder, lubricant, inert
diluent, preservative, surface-active or dispersing agent. Molded tablets
may be made by molding in a suitable machine a mixture of the powdered
compound moistened with an inert liquid diluent. The tablets optionally
may be coated or scored and may be formulated so as to provide slow or
controlled release of the active ingredient therein. Methods of
formulating such slow or controlled release compositions of
pharmaceutically active ingredients, such as those herein and other
compounds known in the art, are known in the art and described in several
issued US Patents, some of which include, but are not limited to, U.S.
Pat. Nos. 4,369,174 and 4,842,866, and references cited therein. Coatings
can be used for delivery of compounds to the intestine (see, e.g. , U.S.
Pat. Nos. 6,638,534, 5,217,720 and 6,569,457, and references cited
therein). A skilled artisan will recognize that in addition to tablets,
other dosage forms can be formulated to provide slow or controlled
release of the active ingredient. Such dosage forms include, but are not
limited to, capsules, granulations and gel-caps.

[0111] Compositions suitable for topical administration include lozenges
comprising the ingredients in a flavored basis, usually sucrose and
acacia or tragacanth; and pastilles comprising the active ingredient in
an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0112] Compositions suitable for parenteral administration include aqueous
and non-aqueous sterile injection solutions which may contain
anti-oxidants, buffers, bacteriostats and solutes which render the
formulation isotonic with the blood of the intended recipient; and
aqueous and non-aqueous sterile suspensions which may include suspending
agents and thickening agents. The formulations may be presented in
unit-dose or multi-dose containers, for example, sealed ampules and
vials, and may be stored in a freeze dried (lyophilized) condition
requiring only the addition of the sterile liquid carrier, for example
water for injections, immediately prior to use.

[0113] Extemporaneous injection solutions and suspensions may be prepared
from sterile powders, granules and tablets.

[0114] Administration of the compounds or compositions to an individual
may involve systemic exposure or may be local administration, such as
when a compound or composition is to be administered at the site of
interest. Various techniques can be used for providing the subject
compositions at the site of interest, such as via injection, use of
catheters, trocars, projectiles, pluronic gel, stems, sustained drug
release polymers or other device which provides for internal access.
Where an organ or tissue is accessible because of removal from the
patient, such organ or tissue may be bathed in a medium containing the
subject compositions, the subject compositions may be painted onto the
organ, or may be applied in any convenient way. The methods of the
invention embrace administration of the compounds to an organ to be
donated (such as to prevent ischemia/reperfusion injury). Accordingly,
organs that are removed from one individual for transplant into another
individual may be bathed in a medium containing or otherwise exposed to a
compound or composition as described herein.

[0115] The compounds of the invention, such as those of the formulae
herein, may be administered in any suitable dosage amount, which may
include dosage levels of about 0.0001 to 4.0 grams once per day (or
multiple doses per day in divided doses) for adults. Thus, in certain
embodiments of this invention, a compound herein is administered at a
dosage of any dosage range in which the low end of the range is any
amount between 0.1 mg/day and 400 mg/day and the upper end of the range
is any amount between 1 mg/day and 4000 mg/day (e.g., 5 mg/day and 100
mg/day, 150 mg/day and 500 mg/day). In other embodiments, a compound
herein, is administered at a dosage of any dosage range in which the low
end of the range is any amount between 0.1 mg/kg/day and 90 mg/kg/day and
the upper end of the range is any amount between 1 mg/kg/day and -32 1 00
mg/kg/day (e.g., 0.5 mg/kg/day and 2 mg/kg/day, 5 mg/kg/day and 20
mg/kg/day). The dosing interval can be adjusted according to the needs of
the individual. For longer intervals of administration, extended release
or depot formulations can be used. The dosing can be commensurate with
intravenous administration. For instance, the compound can be
administered, such as in a pharmaceutical composition that is amenable to
intravenous administration, in an amount of between about 0.01
μg/kg/min to about 100 μg/kg/min or between about 0.05 μg/kg/min
to about 95 μg/kg/min or between about 0.1 μg/kg/min to about 90
μg/kg/min or between about 1.0 μg/kg/min to about 80 μg/kg/min
or between about 10.0 μg/kg/min to about 70 μg/kg/min or between
about 20 μg/kg/min to about 60 μg/kg/min or between about 30
μg/kg/min to about 50 μg/kg/min or between about 0.01 μg/kg/min
to about 1.0 μg/kg/min or between about 0.01 μg/kg/min to about 10
μg/kg/min or between about 0.1 μg/kg/min to about 1.0 μg/kg/min
or between about 0.1 μg/kg/min to about 10 μg/kg/min or between
about 1.0 μg/kg/min to about 5 μg/kg/min or between about 70
μg/kg/min to about 100 μg/kg/min or between about 80 μg/kg/min
to about 90 μg/kg/min. In one variation, the compound is administered
to an individual, such as in a pharmaceutical composition that is
amenable to intravenous administration, in an amount of at least about
0.01 μg/kg/min or at least about 0.05 μg/kg/min or at least about
0.1 μg/kg/min or at least about 0.15 μg/kg/min or at least about
0.25 μg/kg/min or at least about 0.5 μg/kg/min or at least about
1.0 μg/kg/min or at least about 1.5 μg/kg/min or at least about 5.0
μg/kg/min or at least about 10.0 μg/kg/min or at least about 20.0
μg/kg/min or at least about 30.0 μg/kg/min or at least about 40.0
μg/kg/min or at least about 50.0 μg/kg/min or at least about 60.0
μg/kg/min or at least about 70.0 μg/kg/min or at least about 80.0
μg/kg/min or at least about 90.0 μg/kg/min or at least about 100.0
μg/kg/min or more. In another variation, the compound is administered
to an individual, such as in a pharmaceutical composition that is
amenable to intravenous administration, in an amount of less than about
100.0μg/kg/min or less than about 90.0 μg/kg/min or less than about
80.0 μg/kg/min or less than about 80.0 μg/kg/min or less than about
70.0 μg/kg/min or less than about 60.0 μg/kg/min or less than about
50.0 μg/kg/min or less than about 40.0 μg/kg/min or less than about
30.0 μg/kg/min or less than about 20.0μg/kg/min or less than about
10.0 μg/kg/min or less than about 5.0 μg/kg/min or less than about
2.5 μg/kg/min or less than about 1.0 μg/kg/min or less than about
0.5 μg/kg/min or less than about 0.05 μg/kg/min or less than about
0.15 μg/kg/min or less than about 0.1 μg/kg/min or less than about
0.05 μg/kg/min or less than about 0.01 μg/kg/min.

[0116] The invention further provides kits comprising one or more
compounds as described herein. The kits may employ any of the compounds
disclosed herein and instructions for use. The compound may be formulated
in any acceptable form. The kits may be used for any one or more of the
uses described herein, and, accordingly, may contain instructions for any
one or more of the stated uses (e.g., treating and/or preventing and/or
delaying the onset and/or the development of heart failure or
ischemia/reperfusion injury).

[0117] Kits generally comprise suitable packaging. The kits may comprise
one or more containers comprising any compound described herein. Each
component (if there is more than one component) can be packaged in
separate containers or some components can be combined in one container
where cross-reactivity and shelf life permit.

[0118] The kits may optionally include a set of instructions, generally
written instructions, although electronic storage media (e.g., magnetic
diskette or optical disk) containing instructions are also acceptable,
relating to the use of component(s) of the methods of the present
invention (e.g., treating, preventing and/or delaying the onset and/or
the development of heart disease or ischemia/reperfusion injury). The
instructions included with the kit generally include information as to
the components and their administration to an individual.

[0119] The following examples are provided to illustrate various
embodiments of the invention, and are not intended to limit the invention
in any manner.

[0128] Using the experimental conditions reported above and detailed in
General Synthesis Scheme A and B (Methods 1 and 2) and the appropriate
starting materials, which were either commercially available or
synthesised using standard literature conditions, the following
derivatives were prepared:

[0129] The sulfonyl chlorides were synthesised from commercially available
starting materials following the methods described in J. Med. Chem, 40,
2017; Bioorg. Med. Chem, 2002, 639-656; Journal of Pharmacy and
Pharmacology, 1963, 202-211 and in Australian Journal of Chemistry, 2000,
1-6. For example, certain sulfonyl chlorides can be synthesized according
to the following schemes:

##STR00110## ##STR00111##

The scheme for thiophene derivatives can be adapted to synthesize similar
pyrrole derivatives.

[0132] 4-Bromo-3-chlorosulfonyl-benzoic acid (2 g, 6.68 mmol) was
suspended in toluene (20 ml). Thionyl chloride (0.97 ml, 13.36 mmol) was
added drop wise, and the mixture was heated to reflux for 14 hours under
nitrogen until complete consumption of the carboxylic acid was observed
by LCMS. The reaction mixture was concentrated under vacuum to dryness to
afford the expected acid chloride as a solid (2.12 g, 95% yield). The
compound was used for next step without any further purification or
analysis; TR=2.38.

[0140] Phenyl methanethiol (7.6 ml, 43.5 mmol) was added dropwise to a 25%
solution of NaOMe/MeOH (14.1 g, 65.2 mmol) in MeOH (25 ml). The resulting
thiolate was isolated by concentration in vacuo. The sodium thiolate salt
was dissolved in DMSO (65 ml), and
2-(morpholin-4-ylsulfonyl)chlorobenzene (11.1 g, 43.5 mmol) added
portionwise. The reaction mixture was stirred at ambient temperature for
72 h after which time no starting material was evident. The reaction
mixture was poured into a 2N HCl solution (200 mL) and extracted into DCM
(3×200 ml). The organic portion was dried over sodium sulfate,
filtered and concentrated in vaccuo. The crude material was purified by
column chromatography eluting with heptane:ethyl acetate (8:2 v:v).
(13.7g, 90%), TR=1.00 min.

Step 3:

2-(Morpholin-4-ylsulfonyl)benzene sulfonyl chloride

[0141] Chlorine gas was bubbled into a cooled (0° C.) suspension of
benzyl-2-(morpholin-4-ylsulfonyObenzene sulfide (7.0 g, 1.1 mmol) in
concentrated HCl (70 ml) maintaining an internal temperature below
15° C. until complete consumption of the starting material was
observed (c.a. 45 minutes). After completion of the reaction, nitrogen
was bubbled into the reaction mixture for 15 minutes to remove any excess
chlorine and the reaction was warmed to ambient temperature. The reaction
mixture was poured onto ice and the yellow solid formed was filtered and
washed with ice water. The solid was trituated with heptane, filtered and
washed with heptane and dried under vacuum to yield the crude sulfonyl
chloride as a pale yellow solid which was used directly in the synthesis
of Compound 8.

2-(Morpholin-4-yl)ethyl 4-chloro-3-(chlorosulfonyl)benzoate

##STR00114##

[0143] The synthesis of 4-chloro-3-(chlorosulfonyl)benzoic acid and
2-chloro-5-(dimethyl-4-carbonyObenzenesulfonyl chloride were prepared in
the same manner as detailed in the synthesis of
2-bromo-5-(morpholine-4-carbonyl)-benzenesulfonyl chloride

Step 3

2-(Morpholin-4-yl)ethyl 4-chloro-3-(chlorosulfonyl)benzoate

[0144] To a solution of 4-chloro-3-(chlorosulfonyl)benzoyl chloride (1.0
g, 3.6 mmol) in DCM (10 ml) was added a solution of hydroxy ethyl
morpholine (443 μl, 3.6 mmol) in DCM (1 ml). The reaction mixture was
stirred for 12 h after which time no sulfonyl chloride was observed by
LC-MS. Upon concentration of the crude reaction mixture a solid was
isolated, which was trituated with ether to afford the desired compound
as a brown solid. (1.54 g, 100%)

[0155] The ability of compounds to donate nitroxyl at pH 7.4 in PBS buffer
at 37° C. was assessed. In particular, the compounds were tested
and their nitroxyl donating ability at pH 7.4 in PBS buffer at 37°
C. assessed. Results are provided in Table 4 below and results for
compounds 1-5 are also illustrated in FIG. 1.

Use of an in vitro Model to Determine the Ability of Compounds of the
Invention to Treat, Prevent and/or Delay the Onset and/or the Development
of a Disease or Condition Responsive to Nitroxyl Therapy

[0156] a. Cardiovascular Diseases Or Conditions.

[0157] In vitro models of cardiovascular disease can also be used to
determine the ability of any of the compounds described herein to treat,
prevent and/or delay the onset and/or the development of a cardiovascular
disease or condition in an individual. An exemplary in vitro model of
heart disease is described below.

[0158] In-vitro models could be utilized to look at vasorelaxation
properties of the compounds. Isometric tension in isolated rat thoracic
aortic ring segment can be measured as described previously by Crawford,
J. H., Huang, J, Isbell, T. S., Shiva, S., Chacko, B. K., Schechter, A.,
Darley-Usmar, V. M., Kerby, J. D., Lang, J. D., Krauss, D., Ho, C.,
Gladwin , M. T., Patel, R. P., Blood 2006, 107, 566-575. Upon sacrifice
aortic ring segments are excised and cleansed of fat and adhering tissue.
Vessels are then cut into individual ring segments (2-3 mm in width) and
suspended from a force-displacement transducer in a tissue bath. Ring
segments are bathed at 37 ° C. in a bicarbonate-buffered,
Krebs-Henseleit (K-H) solution of the following composition (mM): NaCl
118; KCl 4.6; NaHCO3 27.2; KH2PO4 1.2; MgSO4 1.2;
CaCl2 1.75; Na2EDTA, 0.03; and glucose 11.1 and perfused
continuously with 21% O2/5% CO2/74% N2. A passive load of
2 g is applied to all ring segments and maintained at this level
throughout the experiments. At the beginning of each experiment,
indomethacin-treated ring segments are depolarized with KCl (70 mM) to
determine the maximal contractile capacity of the vessel. Rings are then
washed extensively and allowed to equilibrate. For subsequent
experiments, vessels are submaximally contracted (50% of KCl response)
with phenylephrine (PE, 3×10-8-10-7 M), and L-NMMA, 0.1
mM, is also added to inhibit eNOS and endogenous NO production. After
tension development reaches a plateau, nitroxyl donating compounds are
added cumulatively to the vessel bath and effects on tension monitored.

[0159] In vitro models can be utilized to determine the effects of
nitroxyl donating compounds in changes in developed force and
intracellular calcium in heart muscles. Developed force and intracellular
calcium can be measured in rat trabeculae from normal or diseased (i.e.
rats with congestive heart failure or hypertrophy) as described
previously (Gao W D, Atar D, Backx P H, Marban E. Circ Res.
1995;76:1036-1048). Rats (Sprague-Dawley, 250-300 g) are used in these
experiments. The rats are anesthetized with pentobarbital (100 mg/kg) via
intra-abdominal injection, the heart exposed by mid-sternotomy, rapidly
excised and placed in a dissection dish. The aorta is cannulated and the
heart perfused retrograde (˜15 mM/min) with dissecting
Krebs-Henseleit (H-K) solution equilibrated with 95% O2 and 5%
CO2. The dissecting K-H solution is composed of (mM): NaCl 120,
NaHCO3 20, KCl 5, MgCl 1.2, glucose 10, CaCl2 0.5, and
2,3-butanedione monoximine (BDM) 20, pH 7.35-7.45 at room temperature
(21-22° C.). Trabeculae from the right ventricle of the heart are
dissected and mounted between a force transducer and a motor arm and
superfused with normal K-H solution (KCl, 5 mM) at a rate of ˜10
ml/min and stimulated at 0.5 Hz. Dimensions of the muscles are measured
with a calibration reticule in the ocular of the dissection microscope
(×40, resolution ˜10 μm).

[0160] Force is measured using a force transducer system and is expressed
in milli newtons per square millimeter of cross-sectional area. Sarcomere
length is measured by laser diffraction. Resting sarcomere length is set
at 2.20-2.30 μm throughout the experiments.

[0161] Intracellular calcium is measured using the free acid form of
fura-2 as described in previous studies (Gao et al., 1994; Backx et aL,
1995; Gao et al., 1998). Fura-2 potassium salt is microinjected
iontophoretically into one cell and allowed to spread throughout the
whole muscle (via gap junctions). The tip of the electrode (˜0.2
μm in diameter) is filled with fura-2 salt (1 mM) and the remainder of
the electrode was filled with 150 mM KCl. After a successful impalement
into a superficial cell in non-stimulated muscle, a hyperpolarizing
current of 5-10 nA is passed continuously for ˜15 min. Fura-2
epifluorescence is measured by exciting at 380 and 340 nm. Fluorescent
light is collected at 510 nm by a photomultiplier tube. The output of
photomultiplier is collected and digitized. Ryanodine (1.0 μM) is used
to enable steady-state activation. After 15 min of exposure to ryanodine,
different levels of tetanizations are induced briefly (˜4-8
seconds) by stimulating the muscles at 10 Hz at varied extracellular
calcium (0.5-20 mM). All experiments are performed at room temperature
(20-22° C.).

b. Diseases or Conditions Implicating Ischemia/Reperfusion.

[0162] In vitro models can also be used to determine the ability of any of
the compounds described herein to treat, prevent and/or delay the onset
and/or the development of a disease or condition implicating
ischemia/reperfusion injury in an individual.

Example 6

Use of in vivo and/or ex vivo Models to Determine the Ability of Compounds
of the Invention to Treat, Prevent and/or Delay the Onset and/or the
Development of a Disease or Condition Responsive to Nitroxyl Therapy

[0163] a. Cardiovascular Diseases or Conditions.

[0164] In vivo models of cardiovascular disease can also be used to
determine the ability of any of the compounds described herein to treat,
prevent and/or delay the onset and/or the development of a cardiovascular
disease or condition in an individual. An exemplary animal model of heart
disease is described below.

[0166] Micromanometer transducers in the left ventricle provide pressure,
while right atrial and descending aortic catheters provide
fluid-pressures and sampling conduits. Endocardial sonomicrometers
(anteriorposterior, septal-lateral) measure short-axis dimensions, a
pneumatic occluder around the inferior vena cave facilitated pre-load
manipulations for pressure-relation analysis. Epicardial pacing leads are
placed on the right atrium, and another pair is placed on the right
ventricle free wall linked to a permanent pacemaker to induce rapid
pacing-cardiac failure. After 10 days of recovery, animals are evaluated
at baseline sinus rhythm and with atrial pacing (120-160 bpm).
Measurements include conscious hemodynamic recordings for cardiac
mechanics.

[0167] Compounds of the invention are administrated to a healthy control
dog at the dose of 1-5 μg/kg/min and the resulting cardiovascular data
is obtained.

[0169] The values for test compounds are obtained after 15 min continuous
i.v. infusion (2.5 or 1.25 μg/kg/min) in control and heart failure
preparations, respectively, both in the absence and in the presence of
volume restoration. For comparison, the same hemodynamic measurements are
obtained with AS in heart failure preparations.

b. Diseases or Conditions Implicating Ischemia/Reperfusion.

[0170] Ex-vivo models of ischemia/reperfusion can also be used to
determine the ability of any of the compounds described herein to treat,
prevent and/or delay the onset and/or the development of a disease or
condition implicating ischemia/reperfusion injury in an individual. An
exemplary ex vivo model of ischemia/reperfusion injury is described
below.

[0171] Male Wistar rats are housed in identical cages and allowed access
to tap water and a standard rodent diet ad libitum. Each animal is
anesthetized with 1 g/kg urethane i.p. 10 min after heparin (2,500 U,
i.m.) treatment. The chest is opened, and the heart is rapidly excised,
placed in ice-cold buffer solution and weighed. Isolated rat hearts are
attached to a perfusion apparatus and retrogradely perfused with
oxygenated buffer solution at 37° C. The hearts are instrumented
as previously described in Rastaldo et al., "P-450 metabolite of
arachidonic acid mediates bradykinin-induced negative inotropic effect,"
Am. J. Physiol., 280:H2823-H2832 (2001), and Paolocci et al.
"cGMP-independent inotropic effects of nitric oxide and peroxynitrite
donors: potential role for nitrosylation," Am. J. Physiol., 279:
H1982-H1988 (2000). The flow is maintained constant (approximately 9
mL/min/g wet weight) to reach a typical coronary perfusion pressure of
85-90 mm Hg. A constant proportion of 10% of the flow rate is applied by
means of one of two perfusion pumps (Terumo, Tokyo, Japan) using a 50 mL
syringe connected to the aortic cannula. Drug applications are performed
by switching from the syringe containing buffer alone to the syringe of
the other pump containing the drug (nitroxyl donating compound) dissolved
in a vehicle at a concentration 10× to the desired final
concentration in the heart. A small hole in the left ventricular wall
allows drainage of the thebesian flow, and a polyvinyl-chloride balloon
is placed into the left ventricle and connected to an electromanometer
for recording of left ventricular pressure (LVP). The hearts are
electrically paced at 280-300 bpm and kept in a temperature-controlled
chamber (37° C.). Coronary perfusion pressure (CPP) and coronary
flow are monitored with a second electromanometer and an electromagnetic
flow-probe, respectively, both placed along the perfusion line. Left
ventricular pressure, coronary flow and coronary perfusion pressure are
recorded using a TEAC R-71 recorder, digitized at 1000 Hz and analyzed
off-line with DataQ-Instruments/CODAS software, which allow
quantification of the maximum rate of increase of LVP during systole
(dP/dtmax).

[0174] Experimental Protocols. Hearts are allowed to stabilize for 30 min,
and baseline parameters are recorded. Typically, coronary flow is
adjusted within the first 10 min and kept constant from thereon. After 30
min stabilization, hearts are randomly assigned to one of the treatment
groups, and subjected to 30 min global, no-flow ischemia, followed by 30
min of reperfusion (I/R). Pacing of the hearts is stopped at the
beginning of the ischemic period and restarted after the third minute of
reperfusion.

[0175] Hearts in a control group are perfused with buffer for an
additional 29 min after stabilization. Treated hearts are exposed to a
nitroxyl donor (e.g., 1 μM final concentration for about 20 min
followed by a 10 min buffer wash-out period).

[0176] In all hearts pacing is suspended at the onset of ischemia and
restarted 3 minutes following reperfusion. As isolated heart preparations
may deteriorate over time (typically after 2-2.5 hrs perfusion), the
re-flow duration is limited to 30 min in order to minimize the effects
produced by crystalloid perfusion on heart performance, and consistently
with other reports.

[0177] Assessment of ventricular function. To obtain the maximal developed
LVP, the volume of the intra-ventricular balloon is adjusted to an
end-diastolic LVP of 10 mm Hg during the stabilization period, as
reported in Paolocci, supra, and Hare et al., "Pertussis toxin-sensitive
G proteins influence nitric oxide synthase III activity and protein
levels in rat hearts," J. Clin. Invest., 101:1424-31 (1998). Changes in
developed LVP, dP/dtmax and the end-diastolic value induced by the
I/R protocol are continuously monitored. The difference between the
end-diastolic LVP (EDLVP) before the end of the ischemic period and
during pre-ischemic conditions is used as an index of the extent of
contracture development. Maximal recovery of developed LVP and
dP/dtmax during reperfusion is compared with respective pre-ischemic
values.

[0178] Assessment of myocardial injury. Enzyme release is a measure of
severe myocardial injury that has yet to progress to irreversible cell
injury. Samples of coronary effluent (2 mL) are withdrawn with a catheter
inserted into the right ventricle via the pulmonary artery. Samples are
taken immediately before ischemia and at 3, 6, 10, 20 and 30 min of
reperfusion. LDH release is measured as previously described by Bergmeyer
& Bernt, "Methods of Enzymatic Analysis," Verlag Chemie (1974). Data are
expressed as cumulative values for the entire reflow period.

[0179] To corroborate the data relative to myocardial injury, determined
by LDH release, infarct areas are also assessed in a blinded fashion. At
the end of the course (30 min reperfusion), each heart is rapidly removed
from the perfusion apparatus, and the LV dissected into 2-3 mm
circumferential slices. Following 15 min of incubation at 37° C.
in 0.1% solution of nitro blue tetrazolium in phosphate buffer as
described in Ma et al., "Opposite effects of nitric oxide and nitroxyl on
postischemic myocardial injury," Proc. Natl. Acad. Sci., 96:14617-14622
(1999), unstained necrotic tissue is separated from the stained viable
tissue. The areas of viable and necrotic tissue are carefully separate by
and independent observer who is not aware of the origin of the hearts.
The weight of the necrotic and non-necrotic tissues is then determined
and the necrotic mass expressed as a percentage of total left ventricular
mass.

[0180] Data may be subjected to statistical methods such as ANOVA followed
by the Bonferroni correction for post hoc t tests.

Example 7

Use of Human Clinical Trials to Determine the Ability to Combination
Therapies of the Invention to Treat, Prevent and/or Delay the Onset
and/or the Development of a Disease or Condition Responsive to Nitroxyl
Therapy

[0181] If desired, any of the compounds described herein can also be
tested in humans to determine the ability of the compound to treat,
prevent and/or delay the onset and/or the development of a disease or
condition responsive to nitroxyl therapy. Standard methods can be used
for these clinical trials. In one exemplary method, subjects with such a
disease or condition, such as congestive heart failure, are enrolled in a
tolerability, pharmacokinetics and pharmacodynamics phase I study of a
therapy using the compounds of the invention in standard protocols. Then
a phase II, double-blind randomized controlled trial is performed to
determine the efficacy of the compounds using standard protocols.

[0182] Although the foregoing invention has been described in some detail
by way of illustration and example for purposes of clarity of
understanding, it is apparent to those skilled in the art that certain
minor changes and modifications will be practiced. Therefore, the
description and examples should not be construed as limiting the scope of
the invention.

[0183] All references, publications, patents, and patent applications
disclosed herein are hereby incorporated by reference in their
entireties.